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  • 1051.
    Wikström, Ingela
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap.
    Molecular genetics of B- and T-lymphocyte development2006Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Lymphocytes are essential for the generation of specific immunity. Development of B cells in the bone marrow and T cells in the thymus have several analogous features, and are tightly regulated processes. Even though there is an increasing amount of information concerning lymphopoiesis, a lot of questions remain. The aim of this thesis has been to understand some of the molecular events that contribute to the control of lymphocyte development.

    Expression of the B cell receptor is an important checkpoint in B lymphocyte development. The Dµ protein is a truncated B cell receptor that can induce some of the signals elicited by full length µ, but cannot promote further B cell differentiation. In order to determine if this could stem from an impaired survival signal, we introduced Bcl-2 into RAG2 deficient Dµ transgenic mice. Analysis of these mice showed that Dµ could not support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, data from recombination competent Dµ transgenic mice demonstrated that the Dµ induced partial block is permissive for marginal zone B cell development, whereas the formation of follicular B cells is severely reduced.

    The bHLH family of transcription factors is known to be involved in the regulation of lymphocyte development. Whereas the roles of E2A and HEB have been well documented in both B- and T-lymphocytes, detailed knowledge concerning E2-2 is lacking. To address the role of E2-2 in B cell development, we have reconstituted mice, using E2-2 deficient fetal liver cells, and analysed the B cell compartments. We also measured mRNA expression patterns for the three E-proteins in wildtype mice. Resulting data show that, in addition to a role in B cell lineage entry, E2-2 is required for efficient expansion of pro-B cells, and also influences the follicular versus marginal zone decision.

    While focusing on assigning a role for E2-2 in T-cell development, we analyzed the expression of the E-proteins during this process and performed functional studies in fetal thymic organ cultures. E2-2 deficient mouse embryos were shown to display a partial block at the DN3 stage, which was not due to proliferation or apoptosis defects. In addition, analysis of expression levels of the pre-Talpha chain suggests that E2-2 may play a role in the regulation of transcription of pre-Talpha, and therefore in the assembly of the pre-T cell receptor.

  • 1052.
    Wikström, Ingela
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Penha-Goncalves, Mario
    Forssell, Johan
    Bergqvist, Ingela
    Holmberg, Dan
    A non-redundant role for the bHLH transcription factor E2-2 in early thymocyte developmentManuskript (preprint) (Annet vitenskapelig)
  • 1053.
    Wilbe, Maria
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ekvall, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eurenius, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Ericson, Katharina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Casar-Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Annerén, Göran
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Bondeson, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    MuSK: a new target for lethal fetal akinesia deformation sequence (FADS).2015Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, nr 3, s. 195-202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS.

    METHODS AND RESULTS: We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency.

    CONCLUSIONS: To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.

  • 1054.
    Wilbe, Maria
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gudmundsson, Sanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden..
    Johansson, Josefin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stattin, Eva-Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Annerén, Göran
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Malmgren, Helena
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Frykholm, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bondeson, Marie-Louise
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders2017Inngår i: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, nr 11, s. 1146-1154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective

    De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

    Methods

    We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

    Results

    In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk.

    Conclusions

    Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.

  • 1055. Wilbe, Maria
    et al.
    Kozyrev, Sergey V.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Farias, Fabiana H. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bremer, Hanna D.
    Hedlund, Anna
    Pielberg, Gerli R.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Seppala, Eija H.
    Gustafson, Ulla
    Lohi, Hannes
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Andersson, Goran
    Hansson-Hamlin, Helene
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease2015Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 6, artikkel-id e1005248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAM-TOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.

  • 1056.
    Willander, Kerstin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Chaireti, Roza
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Medicinska akutkliniken.
    Paul, Esbjörn
    Division of Hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Mutations in the isocitrate dehydrogenase 1/2 genes and IDH1 SNP 105C>T have a prognostic value in acute myeloid leukemia2014Inngår i: Biomarker Research, ISSN 2050-7771, Vol. 2, nr 18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The isocitrate dehydrogenase (IDH1/IDH2) genes are frequently mutated and reported to associate with poor prognosis in acute myeloid leukemia (AML). We have investigated the frequency and outcome of the acquired IDH1/IDH2 mutations and the IDH1 SNP  105C>T (rs11554137) in 207 unselected de novo AML patients. IDH1 codon 132 mutations were present in 7.7%, whereas IDH2 mutations were more frequent and mutations were identified in codon 140 and 172 in a frequency of 10.1% and 2.9%, respectively. The SNP 105C>T was present in 10.1% of the patients, similar to the normal population. A significantly reduced overall survival (OS) for patients carrying IDH2 codon 140 mutation compared with patients carrying wild-type IDH2 gene (p=0.009) was observed in the intermediate risk patient group with cytogenetically normal karyotype (CN-AML). Neither in the entire patient group nor subdivided in different risk groups, IDH1 mutations had any significance on OS compared to the wild-type IDH1 patients. A significant difference in OS between the heterozygous SNP variant and the homozygous wild-type was observed in the intermediate risk FLT3 negative CN-AML, (p=0.007). Our results indicate that IDH2 mutations and the IDH1 SNP 105C>T variant may represent a new subgroup for risk stratification and may indicate new treatment options.

  • 1057.
    Willems, Els
    et al.
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Guerrero-Bosagna, Carlos
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Decuypere, Eddy
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Janssens, Steven
    KU Leuven, Department of Biosystems, Research Group Livestock Genetics, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Buyse, Johan
    KU Leuven, Department of Biosystems, Laboratory of Livestock Physiology, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Buys, Nadine
    KU Leuven, Department of Biosystems, Research Group Livestock Genetics, Kasteelpark Arenberg 30 box 2456, 3001 Leuven, Belgium.
    Jensen, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    Everaert, Nadia
    4University of Liège, Gembloux Agro-Bio Tech, Precision Livestock and Nutrition Unit, Passage des Déportés 2, 5030 Gembloux, Belgium.
    Differential Expression of Genes and DNA Methylation associated with Prenatal Protein Undernutrition by Albumen Removal in an avian model2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previously, long-term effects on body weight and reproductive performance have been demonstrated in the chicken model of prenatal protein undernutrition by albumen removal. Introduction of such persistent alterations in phenotype suggests stable changes in gene expression. Therefore, a genome-wide screening of the hepatic transcriptome by RNA-Seq was performed in adult hens. The albumen-deprived hens were created by partial removal of the albumen from eggs and replacement with saline early during embryonic development. Results were compared to sham-manipulated hens and non-manipulated hens. Grouping of the differentially expressed (DE) genes according to biological functions revealed the involvement of processes such as 'embryonic and organismal development' and 'reproductive system development and function'. Molecular pathways that were altered were 'amino acid metabolism', 'carbohydrate metabolism' and 'protein synthesis'. Three key central genes interacting with many DE genes were identified: UBC, NR3C1, and ELAVL1. The DNA methylation of 9 DE genes and 3 key central genes was examined by MeDIP-qPCR. The DNA methylation of a fragment (UBC_3) of the UBC gene was increased in the albumen-deprived hens compared to the non-manipulated hens. In conclusion, these results demonstrated that prenatal protein undernutrition by albumen removal leads to long-term alterations of the hepatic transcriptome in the chicken.

  • 1058. Willems, Sara M.
    et al.
    Wright, Daniel J.
    Day, Felix R.
    Trajanoska, Katerina
    Joshi, Peter K.
    Morris, John A.
    Matteini, Amy M.
    Garton, Fleur C.
    Grarup, Niels
    Oskolkov, Nikolay
    Thalamuthu, Anbupalam
    Mangino, Massimo
    Liu, Jun
    Demirkan, Ayse
    Lek, Monkol
    Xu, Liwen
    Wang, Guan
    Oldmeadow, Christopher
    Gaulton, Kyle J.
    Lotta, Luca A.
    Miyamoto-Mikami, Eri
    Rivas, Manuel A.
    White, Tom
    Loh, Po-Ru
    Aadahl, Mette
    Amin, Najaf
    Attia, John R.
    Austin, Krista
    Benyamin, Beben
    Brage, Soren
    Cheng, Yu-Ching
    Cieszczyk, Pawel
    Derave, Wim
    Eriksson, Karl-Fredrik
    Eynon, Nir
    Linneberg, Allan
    Lucia, Alejandro
    Massidda, Myosotis
    Mitchell, Braxton D.
    Miyachi, Motohiko
    Murakami, Haruka
    Padmanabhan, Sandosh
    Pandey, Ashutosh
    Papadimitriou, Loannis
    Rajpal, Deepak K.
    Sale, Craig
    Schnurr, Theresia M.
    Sessa, Francesco
    Shrine, Nick
    Tobin, Martin D.
    Varley, Ian
    Wain, Louise V.
    Wray, Naomi R.
    Lindgren, Cecilia M.
    MacArthur, Daniel G.
    Waterworth, Dawn M.
    McCarthy, Mark I.
    Pedersen, Oluf
    Khaw, Kay-Tee
    Kie, Douglas P.
    Pitsiladis, Yannis
    Fuku, Noriyuki
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skånes University Hospital, 222 41 Lund, Sweden.
    North, Kathryn N.
    van Duijn, Cornelia M.
    Mather, Karen A.
    Hansen, Torben
    Hansson, Ola
    Spector, Tim
    Murabito, Joanne M.
    Richards, J. Brent
    Rivadeneira, Fernando
    Langenberg, Claudia
    Perry, John R. B.
    Wareham, Nick J.
    Scott, Robert A.
    Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness2017Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 16015Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 x 10(-8)) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

  • 1059. Willer, Cristen J.
    et al.
    Schmidt, Ellen M.
    Sengupta, Sebanti
    Peloso, Gina M.
    Gustafsson, Stefan
    Kanoni, Stavroula
    Ganna, Andrea
    Chen, Jin
    Buchkovich, Martin L.
    Mora, Samia
    Beckmann, Jacques S.
    Bragg-Gresham, Jennifer L.
    Chang, Hsing-Yi
    Demirkan, Ayse
    Den Hertog, Heleen M.
    Do, Ron
    Donnelly, Louise A.
    Ehret, Georg B.
    Esko, Tonu
    Feitosa, Mary F.
    Ferreira, Teresa
    Fischer, Krista
    Fontanillas, Pierre
    Fraser, Ross M.
    Freitag, Daniel F.
    Gurdasani, Deepti
    Heikkila, Kauko
    Hyppoenen, Elina
    Isaacs, Aaron
    Jackson, Anne U.
    Johansson, Asa
    Johnson, Toby
    Kaakinen, Marika
    Kettunen, Johannes
    Kleber, Marcus E.
    Li, Xiaohui
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Magnusson, Patrik K. E.
    Mangino, Massimo
    Mihailov, Evelin
    Montasser, May E.
    Mueller-Nurasyid, Martina
    Nolte, Ilja M.
    O'Connell, Jeffrey R.
    Palmer, Cameron D.
    Perola, Markus
    Petersen, Ann-Kristin
    Sanna, Serena
    Saxena, Richa
    Service, Susan K.
    Shah, Sonia
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Lunds universitet.
    Sidore, Carlo
    Song, Ci
    Strawbridge, Rona J.
    Surakka, Ida
    Tanaka, Toshiko
    Teslovich, Tanya M.
    Thorleifsson, Gudmar
    Van den Herik, Evita G.
    Voight, Benjamin F.
    Volcik, Kelly A.
    Waite, Lindsay L.
    Wong, Andrew
    Wu, Ying
    Zhang, Weihua
    Absher, Devin
    Asiki, Gershim
    Barroso, Ines
    Been, Latonya F.
    Bolton, Jennifer L.
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Burnett, Mary S.
    Cesana, Giancarlo
    Dimitriou, Maria
    Doney, Alex S. F.
    Doering, Angela
    Elliott, Paul
    Epstein, Stephen E.
    Eyjolfsson, Gudmundur Ingi
    Gigante, Bruna
    Goodarzi, Mark O.
    Grallert, Harald
    Gravito, Martha L.
    Groves, Christopher J.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Hernandez, Dena
    Hicks, Andrew A.
    Holm, Hilma
    Hung, Yi-Jen
    Illig, Thomas
    Jones, Michelle R.
    Kaleebu, Pontiano
    Kastelein, John J. P.
    Khaw, Kay-Tee
    Kim, Eric
    Klopp, Norman
    Komulainen, Pirjo
    Kumari, Meena
    Langenberg, Claudia
    Lehtimaki, Terho
    Lin, Shih-Yi
    Lindstrom, Jaana
    Loos, Ruth J. F.
    Mach, Francois
    McArdle, Wendy L.
    Meisinger, Christa
    Mitchell, Braxton D.
    Mueller, Gabrielle
    Nagaraja, Ramaiah
    Narisu, Narisu
    Nieminen, Tuomo V. M.
    Nsubuga, Rebecca N.
    Olafsson, Isleifur
    Ong, Ken K.
    Palotie, Aarno
    Papamarkou, Theodore
    Pomilla, Cristina
    Pouta, Anneli
    Rader, Daniel J.
    Reilly, Muredach P.
    Ridker, Paul M.
    Rivadeneira, Fernando
    Rudan, Igor
    Ruokonen, Aimo
    Samani, Nilesh
    Scharnagl, Hubert
    Seeley, Janet
    Silander, Kaisa
    Stancakova, Alena
    Stirrups, Kathleen
    Swift, Amy J.
    Tiret, Laurence
    Uitterlinden, Andre G.
    van Pelt, L. Joost
    Vedantam, Sailaja
    Wainwright, Nicholas
    Wijmenga, Cisca
    Wild, Sarah H.
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wilson, James F.
    Young, Elizabeth H.
    Zhao, Jing Hua
    Adair, Linda S.
    Arveiler, Dominique
    Assimes, Themistocles L.
    Bandinelli, Stefania
    Bennett, Franklyn
    Bochud, Murielle
    Boehm, Bernhard O.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    Bornstein, Stefan R.
    Bovet, Pascal
    Burnier, Michel
    Campbell, Harry
    Chakravarti, Aravinda
    Chambers, John C.
    Chen, Yii-Der Ida
    Collins, Francis S.
    Cooper, Richard S.
    Danesh, John
    Dedoussis, George
    de Faire, Ulf
    Feranil, Alan B.
    Ferrieres, Jean
    Ferrucci, Luigi
    Freimer, Nelson B.
    Gieger, Christian
    Groop, Leif C.
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hamsten, Anders
    Harris, Tamara B.
    Hingorani, Aroon
    Hirschhorn, Joel N.
    Hofman, Albert
    Hovingh, G. Kees
    Hsiung, Chao Agnes
    Humphries, Steve E.
    Hunt, Steven C.
    Hveem, Kristian
    Iribarren, Carlos
    Jarvelin, Marjo-Riitta
    Jula, Antti
    Kahonen, Mika
    Kaprio, Jaakko
    Kesaniemi, Antero
    Kivimaki, Mika
    Kooner, Jaspal S.
    Koudstaal, Peter J.
    Krauss, Ronald M.
    Kuh, Diana
    Kuusisto, Johanna
    Kyvik, Kirsten O.
    Laakso, Markku
    Lakka, Timo A.
    Lind, Lars
    Lindgren, Cecilia M.
    Martin, Nicholas G.
    Maerz, Winfried
    McCarthy, Mark I.
    McKenzie, Colin A.
    Meneton, Pierre
    Metspalu, Andres
    Moilanen, Leena
    Morris, Andrew D.
    Munroe, Patricia B.
    Njolstad, Inger
    Pedersen, Nancy L.
    Power, Chris
    Pramstaller, Peter P.
    Price, Jackie F.
    Psaty, Bruce M.
    Quertermous, Thomas
    Rauramaa, Rainer
    Saleheen, Danish
    Salomaa, Veikko
    Sanghera, Dharambir K.
    Saramies, Jouko
    Schwarz, Peter E. H.
    Sheu, Wayne H-H
    Shuldiner, Alan R.
    Siegbahn, Agneta
    Spector, Tim D.
    Stefansson, Kari
    Strachan, David P.
    Tayo, Bamidele O.
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van Duijn, Cornelia M.
    Vollenweider, Peter
    Wallentin, Lars
    Wareham, Nicholas J.
    Whitfield, John B.
    Wolffenbuttel, Bruce H. R.
    Ordovas, Jose M.
    Boerwinkle, Eric
    Palmer, Colin N. A.
    Thorsteinsdottir, Unnur
    Chasman, Daniel I.
    Rotter, Jerome I.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lunds universitet, Harvard University.
    Ripatti, Samuli
    Cupples, L. Adrienne
    Sandhu, Manjinder S.
    Rich, Stephen S.
    Boehnke, Michael
    Deloukas, Panos
    Kathiresan, Sekar
    Mohlke, Karen L.
    Ingelsson, Erik
    Abecasis, Goncalo R.
    Discovery and refinement of loci associated with lipid levels2013Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 11, s. 1274-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

  • 1060.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Stattin, Eva-Lena
    Westin, Ida Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis2017Inngår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, artikkel-id 74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1APsequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations.

    Methods: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs.

    Results: A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males.

    Conclusions: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.

  • 1061.
    Winkler, Thomas W.
    et al.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Justice, Anne E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Graff, Mariaelisa
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Barata, Llilda
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Chu, Su
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Czajkowski, Jacek
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Esko, Tonu
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Kilpelainen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Pers, Tune H.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA USA..
    Rueeger, Sina
    Swiss Inst Bioinformat, Lausanne, Switzerland.;Univ Hosp Lausanne CHUV, Inst Social & Prevent Med, Lausanne, Switzerland..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany..
    Ehret, Georg B.
    Univ Hosp Geneva, Dept Specialties Internal Med, Geneva, Switzerland.;Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Heard-Costa, Nancy L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Karjalainen, Juha
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Lagou, Vasiliki
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Neinast, Michael D.
    Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Hammersmith Hosp, London, England.;Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Simino, Jeannette
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jansen, Rick
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Westra, Harm-Jan
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Partners Ctr Personalized Genet Med, Boston, MA USA..
    White, Charles C.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Absher, Devin
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Ahluwalia, Tarunveer S.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Steno Diabet Ctr A S, Gentofte, Denmark.;Univ Copenhagen, Herlev & Gentofte Hosp, COPSAC, Copenhagen, Denmark..
    Ahmad, Shafqat
    Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Albrecht, Eva
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    Alves, Alexessander Couto
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England..
    Bragg-Gresham, Jennifer L.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    de Craen, Anton J. M.
    Leiden Univ Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Bis, Joshua C.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA 98195 USA..
    Bonnefond, Amelie
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Boucher, Gabrielle
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Cadby, Gemma
    Univ Western Australia, Ctr Genet Origins Hlth & Dis, Crawley, WA, Australia..
    Cheng, Yu-Ching
    VA Maryland Hlth Care Syst, Baltimore, MD USA.;Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA..
    Chiang, Charleston W. K.
    Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA USA..
    Delgado, Graciela
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany..
    Demirkan, Ayse
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Dueker, Nicole
    Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA..
    Eklund, Niina
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Eiriksdottir, Gudny
    Iceland Heart Assoc, Kopavogur, Iceland..
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Feenstra, Bjarke
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Frau, Francesca
    Univ Milan, Dept Hlth Sci, Milan, Italy.;Filarete Fdn, Genom & Bioinformat Unit, Milan, Italy..
    Galesloot, Tessel E.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands..
    Geller, Frank
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Goel, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Gorski, Mathias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Grammer, Tanja B.
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany..
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Haitjema, Saskia
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Huffman, Jennifer E.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jacobs, Kevin B.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.;NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA..
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Kaakinen, Marika
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPA Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland..
    Kleber, Marcus E.
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany..
    Lahti, Jari
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Inst Behav Sci, Helsinki, Finland..
    Leach, Irene Mateo
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Lehne, Benjamin
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Liu, Youfang
    Univ N Carolina Chapel Hill, Thurston Arthrit Res Ctr, Chaper Hill, NC USA..
    Lo, Ken Sin
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Luan, Jian'an
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Madden, Pamela A. F.
    Washington Univ, Sch Med, St Louis, MO USA..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    McKnight, Barbara
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98104 USA.;Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Medina-Gomez, Carolina
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Monda, Keri L.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA.;Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA..
    Montasser, May E.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Mueller, Gabriele
    Univ Dresden, Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, Dresden, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.;Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, D-81377 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Panoutsopoulou, Kalliope
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Pascoe, Laura
    Newcastle Univ, Inst Cell & Mol Biosci, Newcastle, NSW, Australia..
    Paternoster, Lavinia
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England..
    Rayner, Nigel W.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Renstrom, Frida
    Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Rizzi, Federica
    Univ Milan, Dept Hlth Sci, Milan, Italy.;Filarete Fdn, Genom & Bioinformat Unit, Milan, Italy..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Ryan, Kathy A.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Salo, Perttu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland..
    Sanna, Serena
    CNR, Ist Ric Genet & Biomed, Monserrato, Italy..
    Scharnagl, Hubert
    Med Univ Graz, Inst Clin Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria..
    Shi, Jianxin
    NCI, Bethesda, MD 20892 USA..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Southam, Lorraine
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Stancakova, Alena
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Steinthorsdottir, Valgerdur
    Amgen Inc, deCODE Genet, Reykjavik, Iceland..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden..
    Sung, Yun Ju
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Tachmazidou, Ioanna
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Tanaka, Toshiko
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    Thorleifsson, Gudmar
    Amgen Inc, deCODE Genet, Reykjavik, Iceland..
    Trompet, Stella
    Leiden Univ Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands.;Leiden Univ Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland.;Univ Tartu, Inst Cell & Mol Biol, Dept Biotechnol, EE-50090 Tartu, Estonia.;Univ Helsinki, Helsinki, Finland..
    Tyrer, Jonathan P.
    Univ Cambridge, Dept Oncol, Cambridge, England..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    van der Laan, Sander W.
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Internal Med, Geriatr Med Sect, NL-1105 AZ Amsterdam, Netherlands..
    van Setten, Jessica
    Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands..
    van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Vlachopoulou, Efthymia
    Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland..
    Waite, Lindsay L.
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Wang, Sophie R.
    Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Program Genom, Boston, MA USA..
    Wang, Zhaoming
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.;NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA..
    Wild, Sarah H.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland..
    Willenborg, Christina
    Hamburg Kiel Lubeck, DZHK German Ctr Cardiovasc Res, Lubeck, Germany.;Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany..
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    Wong, Andrew
    MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Yang, Jian
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Yengo, Loic
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Yerges-Armstrong, Laura M.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Yu, Lei
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Zhang, Weihua
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Southall, Middx, England..
    Zhao, Jing Hua
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Andersson, Ehm A.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Bakker, Stephan J. L.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Baldassarre, Damiano
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Banasik, Karina
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Barcella, Matteo
    Univ Milan, Dept Hlth Sci, Milan, Italy..
    Barlassina, Cristina
    Univ Milan, Dept Hlth Sci, Milan, Italy..
    Bellis, Claire
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA.;Queensland Univ Technol, Inst Hlth & Biomed Innovat, Genom Res Ctr, Brisbane, Qld 4001, Australia..
    Benaglio, Paola
    Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA.;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Blangero, John
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Blueher, Matthias
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Bonnet, Fabrice
    Univ Rennes 1, Rennes, France..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Boyd, Heather A.
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Bruinenberg, Marcel
    Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands..
    Buchman, Aron S.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    Chen, Yii-Der Ida
    Univ Calif Los Angeles, Med Ctr, Los Angeles BioMed Res Inst Harbor, Torrance, CA 90509 USA..
    Chines, Peter S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Claudi-Boehm, Simone
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Cole, John
    VA Maryland Hlth Care Syst, Baltimore, MD USA.;Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA..
    Collins, Francis S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Dept Human Nutr, NL-6700 AP Wageningen, Netherlands..
    Dimitriou, Maria
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Duan, Jubao
    NorthShore Univ HealthSyst, Evanston, IL USA.;Univ Chicago, Chicago, IL 60637 USA..
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Eury, Elodie
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Farmaki, Aliki-Eleni
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Forouhi, Nita G.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Friedrich, Nele
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany..
    Gejman, Pablo V.
    NorthShore Univ HealthSyst, Evanston, IL USA.;Univ Chicago, Chicago, IL 60637 USA..
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Glorioso, Nicola
    AOU Univ Sassari, Hypertens & Related Dis Ctr, Sassari, Italy..
    Go, Alan S.
    Kaiser Permanente, Div Res, Oakland, CA USA..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA..
    Graessler, Juergen
    Univ Dresden, Dept Med Pathobiochem 3, Dresden, Germany..
    Grallert, Harald
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Gu, Yu-Mei
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium..
    Broer, Linda
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Ham, Annelies C.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA.;NIA, NIH, Bethesda, MD 20892 USA..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Hassinen, Maija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Hastie, Nicholas
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Hattersley, Andrew T.
    Univ Exeter, Inst Biomed & Clin Sci, Exeter, Devon, England..
    Heath, Andrew C.
    Washington Univ, Sch Med, St Louis, MO USA..
    Henders, Anjali K.
    QIMR Bergofer Med Res Inst, Brisbane, Qld, Australia..
    Hernandez, Dena
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Hillege, Hans
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Holmen, Oddgeir
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway..
    Hovingh, Kees G.
    Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands..
    Hui, Jennie
    Pathwest Lab Med Western Australia, Nedlands, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia..
    Husemoen, Lise L.
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark..
    Hutri-Kahonen, Nina
    Univ Tampere, Sch Med, Dept Pediat, FIN-33101 Tampere, Finland.;Tampere Univ Hosp, Dept Pediat, Tampere, Finland..
    Hysi, Pirro G.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Illig, Thomas
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, NH, Germany..
    De Jager, Philip L.
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA..
    Jalilzadeh, Shapour
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Jorgensen, Torben
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Jukema, J. Wouter
    Leiden Univ Med Ctr, Dept Cardiol, Leiden, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Juonala, Markus
    Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland.;Murdoch Childrens Res Inst, Parkville, Vic, Australia.;Univ Turku, Dept Med, Turku, Finland..
    Kanoni, Stavroula
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Karaleftheri, Maria
    Echinos Med Ctr, Echinos, Greece..
    Khaw, Kay Tee
    Addenbrookes Hosp, Clin Gerontol Unit, Cambridge, England..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Kittner, Steven J.
    VA Maryland Hlth Care Syst, Baltimore, MD USA.;Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA..
    Koenig, Wolfgang
    Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany..
    Kolcic, Ivana
    Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Kovacs, Peter
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany..
    Krarup, Nikolaj T.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Kratzer, Wolfgang
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Krueger, Janine
    Univ Med Greifswald, Dept Med A, Greifswald, Germany..
    Kuh, Diana
    MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London, England..
    Kyriakou, Theodosios
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;UCL, Dept Epidemiol & Publ Hlth, London, England..
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lanzani, Chiara
    Univ Vita Salute San Raffaele, Chair Nephrol, Segrate, Milan, Italy.;IRCCS San Raffaele Sci Inst, Genom Renal Dis & Hypertens Unit, Segrate, Milan, Italy..
    Lotay, Vaneet
    Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada..
    Launer, Lenore J.
    NIA, NIH, Bethesda, MD 20892 USA..
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Lindstrom, Jaana
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland..
    Linneberg, Allan
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark..
    Liu, Yan-Ping
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium..
    Lobbens, Stephane
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France..
    Luben, Robert
    Strangeways Res Lab Worts Causeway, Cambridge, England..
    Lyssenko, Valeriya
    Steno Diabet Ctr A S, Gentofte, Denmark.;Lund Univ, Ctr Diabet, Malmo, Sweden.;Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, Malmo, Sweden..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    McArdle, Wendy L.
    Univ Bristol, Sch Social & Community Med, Bristol, Avon, England..
    Menni, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Merger, Sigrun
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Montgomery, Grant W.
    QIMR Bergofer Med Res Inst, Brisbane, Qld, Australia..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England..
    Narisu, Narisu
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Nelis, Mari
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Ong, Ken K.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;MRC Unit Lifelong Hlth & Ageing UCL, London, England.;Univ Cambridge, Dept Paediat, Cambridge, England..
    Palotie, Aarno
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.;Metaanal Glucose & Insulin Related Traits Consort, Beijing, Peoples R China..
    Perusse, Louis
    Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada.;Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada..
    Pichler, Irene
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany..
    Pilia, Maria G.
    CNR, Ist Ric Genet & Biomed, Monserrato, Italy..
    Pouta, Anneli
    Natl Inst Hlth & Welf, Dept Children Young People & Families, Helsinki, Finland.;Oulu Univ Hosp, Med Res Ctr, Dept Obstet & Gynecol, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Rheinberger, Myriam
    Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Ribel-Madsen, Rasmus
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Richards, Marcus
    MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Rice, Kenneth M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Rice, Treva K.
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Rivolta, Carlo
    Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Sanders, Alan R.
    NorthShore Univ HealthSyst, Evanston, IL USA.;Univ Chicago, Chicago, IL 60637 USA..
    Sarzynski, Mark A.
    Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA..
    Scholtens, Salome
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Scott, William R.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Southall, Middx, England..
    Sebert, Sylvain
    Univ Oulu, Inst Hlth Sci, Oulu, Finland..
    Sengupta, Sebanti
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    Seufferlein, Thomas
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden..
    Slagboom, P. Eline
    Leiden Univ Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands..
    Smit, Jan H.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Sparso, Thomas H.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Stirrups, Kathleen
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Stolk, Ronald P.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Swertz, Morris A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Swift, Amy J.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Tan, Sian-Tsung
    Ealing Hosp NHS Trust, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England..
    Thorand, Barbara
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Toenjes, Anke
    Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Tremblay, Angelo
    Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada..
    Tsafantakis, Emmanouil
    Anogia Med Ctr, Anogia, Greece..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Voelker, Uwe
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada.;Univ Laval, Sch Nutr, Quebec City, PQ, Canada..
    Vonk, Judith M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Waldenberger, Melanie
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Walker, Ryan W.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Wennauer, Roman
    Univ Ulm, Med Ctr, Dept Clin Chem, D-89069 Ulm, Germany..
    Widen, Elisabeth
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Wilsgaard, Tom
    Univ Tromso, Fac Hlth Sci, Dept Clin Med, Tromso, Norway.;Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Wright, Alan F.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Zillikens, M. Carola
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    van Dijk, Suzanne C.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    van Schoor, Natasja M.
    Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands..
    Asselbergs, Folkert W.
    Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.;Netherlands Heart Inst, Interuniv Cardiol Inst Netherlands, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.;UCL, Inst Cardiovasc Sci, London, England..
    de Bakker, Paul I. W.
    Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands.;Univ Med Ctr, Dept Epidemiol, Utrecht, Netherlands..
    Beckmann, Jacques S.
    Swiss Inst Bioinformat, Lausanne, Switzerland..
    Beilby, John
    Pathwest Lab Med Western Australia, Nedlands, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Bergmann, Sven
    Swiss Inst Bioinformat, Lausanne, Switzerland.;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Boeger, Carsten A.
    Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Boehm, Bernhard O.
    Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany.;Univ London Imperial Coll Sci Technol & Med, London, England.;Lee Kong Chian Sch Med, Singapore, Singapore.;Nanyang Technol Univ, Singapore 639798, Singapore..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA.;Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Bornstein, Stefan R.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA..
    Bouchard, Claude
    Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA..
    Chambers, John C.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98104 USA..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Cucca, Francesco
    CNR, Ist Ric Genet & Biomed, Monserrato, Italy.;Univ Sassari, I-07100 Sassari, Italy..
    Cusi, Daniele
    Univ Milan, Dept Hlth Sci, Milan, Italy.;Natl Inst Res, Inst Biomed Technol, Segrate, Italy..
    Dedoussis, George
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Erdmann, Jeanette
    Hamburg Kiel Lubeck, DZHK German Ctr Cardiovasc Res, Lubeck, Germany.;Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany..
    Eriksson, Johan G.
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland..
    Evans, Denis A.
    Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Farrall, Martin
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands..
    Ferrucci, Luigi
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Franke, Lude
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Franks, Paul W.
    Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ Hosp, Dept Publ Hlth & Clin Med, Umea, Sweden.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Froguel, Philippe
    CNRS, UMR 8199, Lille, France.;European Genom Inst Diabet, Lille, France.;Univ Lille 2, Lille, France..
    Gansevoort, Ron T.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Gieger, Christian
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Gronberg, Henrik
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.;Netherlands Heart Inst, Interuniv Cardiol Inst Netherlands, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Heliovaara, Markku
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Hengstenberg, Christian
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany..
    Hicks, Andrew A.
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany..
    Hingorani, Aroon
    UCL, Inst Cardiovasc Sci, London, England..
    Hofman, Albert
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Hu, Frank
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Huikuri, Heikki V.
    Oulu Univ Hosp, Med Res Ctr Oulu, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway..
    James, Alan L.
    Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia..
    Jordan, Joanne M.
    Univ N Carolina Chapel Hill, Thurston Arthrit Res Ctr, Chaper Hill, NC USA..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Kaehoenen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, FIN-33101 Tampere, Finland..
    Kajantie, Eero
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland..
    Kathiresan, Sekar
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Kiemeney, Lambertus A. L. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Urol, NL-6525 ED Nijmegen, Netherlands..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London, England..
    Knekt, Paul B.
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Med, Helsinki, Finland.;Abdominal Ctr Endocrinol, Helsinki, Finland.;Minerva Fdn, Helsinki, Finland..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Koskinen, Seppo
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Maerz, Winfried
    Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Mannheim, Germany.;Med Univ Graz, Inst Clin Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria..
    Martin, Nicholas G.
    QIMR Bergofer Med Res Inst, Brisbane, Qld, Australia..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, SF-70210 Kuopio, Finland..
    Lakka, Timo A.
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed, Dept Physiol, Kuopio, Finland..
    Lehtimaki, Terho
    Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland.;Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland.;Univ Tampere, Sch Med, FIN-33101 Tampere, Finland..
    Lettre, Guillaume
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada..
    Levinson, Douglas F.
    Stanford Univ, Stanford, CA 94305 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lokki, Marja-Liisa
    Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland..
    Mantyselka, Pekka
    Univ Eastern Finland, Sch Med, Inst Publ Hlth & Clin Nutr, Primary Hlth Care Unit, Kuopio, Finland.;Kuopio Univ Hosp, Primary Hlth Care Unit, SF-70210 Kuopio, Finland..
    Melbye, Mads
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Mitchell, Braxton D.
    Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA.;Baltimore Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA..
    Moll, Frans L.
    Univ Med Ctr Utrecht, Dept Surg, Utrecht, Netherlands..
    Murray, Jeffrey C.
    Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA..
    Musk, Arthur W.
    Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia..
    Nieminen, Markku S.
    Helsinki Univ Cent Hosp, HUCH Heart & Lung Ctr, Div Cardiol, Helsinki, Finland..
    Njolstad, Inger
    Univ Tromso, Fac Hlth Sci, Dept Clin Med, Tromso, Norway.;Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med,Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Oostra, Ben A.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Palmer, Lyle J.
    Univ Adelaide, Sch Publ Hlth, Adelaide, SA, Australia.;Univ Adelaide, Robinson Res Inst, Adelaide, SA, Australia..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Pasterkamp, Gerard
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark..
    Penninx, Brenda W.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Perola, Markus
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Polasek, Ozren
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.;Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Pramstaller, Peter P.
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Med Univ Lubeck, Affiliated Inst, D-23538 Lubeck, Germany.;Gen Cent Hosp, Dept Neurol, Bolzano, Italy..
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Cooperat, Grp Hlth Res Inst, Seatte, WA USA..
    Qi, Lu
    Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Quertermous, Thomas
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Rankinen, Tuomo
    Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Rioux, John D.
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada..
    Rivadeneira, Fernando
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Rotter, Jerome I.
    Univ Calif Los Angeles, Med Ctr, Los Angeles BioMed Res Inst Harbor, Torrance, CA 90509 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    den Ruijter, Hester M.
    UMCU, Expt Cardiol & Lab Clin Chem, Utrecht, Netherlands..
    Saltevo, Juha
    Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland..
    Sattar, Naveed
    Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland..
    Schunkert, Heribert
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany..
    Schwarz, Peter E. H.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
    Shuldiner, Alan R.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA.;Vetrans Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA..
    Sinisalo, Juha
    Helsinki Univ Cent Hosp, HUCH Heart & Lung Ctr, Div Cardiol, Helsinki, Finland..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Sorensen, Thorkild I. A.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark.;Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England.;Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, Frederiksberg, Denmark..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Staessen, Jan A.
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.;Maastricht Univ, R&D VitaK Grp, Maastricht, Netherlands..
    Stefania, Bandinelli
    ASF, Geriatr Unit, Florence, Italy..
    Thorsteinsdottir, Unnur
    Amgen Inc, deCODE Genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stumvoll, Michael
    Univ Leipzig, IFB Adipos Dis, D-04109 Leipzig, Germany.;Univ Leipzig, Dept Med, D-04109 Leipzig, Germany..
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada..
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;Hosp Univ La Paz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain.;King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia..
    Uitterlinden, Andre G.
    NCHA, NGI, Leiden, Netherlands.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Uusitupa, Matti
    Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Espoo, Finland.;Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland..
    Verbeek, Andre L. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands..
    Vermeulen, Sita H.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands..
    Viikari, Jorma S.
    Univ Turku, Dept Med, Turku, Finland..
    Vitart, Veronique
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Vollenweider, Peter
    Univ Hosp Lausanne CHUV, Dept Internal Med, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Waeber, Gerard
    Univ Hosp Lausanne CHUV, Dept Internal Med, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Walker, Mark
    Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.;Newcastle Univ, Inst Cellular Med, Newcastle, NSW, Australia..
    Wallaschofski, Henri
    Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Watkins, Hugh
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovac Med, Oxford, England..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England..
    Chakravarti, Aravinda
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Clegg, Deborah J.
    Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA..
    Cupples, L. Adrienne
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Gordon-Larsen, Penny
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA..
    Jaquish, Cashell E.
    NHLBI, NIH, Bethesda, MD 20892 USA..
    Rao, D. C.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Assimes, Themistocles L.
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge, England.;Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England..
    Berndt, Sonja I.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Human Genet, Cambridge, England.;Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, PACER HD, Jeddah 21413, Saudi Arabia..
    Fox, Caroline S.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Groop, Leif C.
    Lund Univ, Ctr Diabet, Malmo, Sweden.;Lund Univ, Dept Clin Sci, Diabet & Endocrinol Unit, Malmo, Sweden.;Univ Helsinki, FIMM, Helsinki, Finland..
    Hunter, David J.
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Kaplan, Robert C.
    Albert Einstein Coll Med, Dept Epidemiol & Popualt Hlth, Bronx, NY 10467 USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford NIHR Biomed Res Ctr, Oxford, England..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    O'Connell, Jeffrey R.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr,Program Personalized, Baltimore, MD 21201 USA..
    Schlessinger, David
    NIA, NIH, Bethesda, MD 20892 USA..
    Strachan, David P.
    St Georges Univ London, Populat Hlth Res Inst, London, England..
    Stefansson, Kari
    Amgen Inc, deCODE Genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.;NCHA, NGI, Leiden, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    Hirschhorn, Joel N.
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Div Genet, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA..
    Lindgren, Cecilia M.
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Heid, Iris M.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    North, Kari E.
    Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA.;Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA..
    Kutalik, Zoltan
    Swiss Inst Bioinformat, Lausanne, Switzerland.;Univ Hosp Lausanne CHUV, Inst Social & Prevent Med, Lausanne, Switzerland.;Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Loos, Ruth J. F.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study2015Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 10, artikkel-id e1005378Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men <= 50y, men > 50y, women <= 50y, women > 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR< 5%) age-specific effects, of which 11 had larger effects in younger (< 50y) than in older adults (>= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

  • 1062. Winkler, Thomas W
    et al.
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    Graff, Mariaelisa
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    Chu, Su
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    Mihailov, Evelin
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    Alves, Alexessander Couto
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    Bis, Joshua C
    Bonnefond, Amélie
    Boucher, Gabrielle
    Cadby, Gemma
    Cheng, Yu-Ching
    Chiang, Charleston W K
    Delgado, Graciela
    Demirkan, Ayse
    Dueker, Nicole
    Eklund, Niina
    Eiriksdottir, Gudny
    Eriksson, Joel
    Feenstra, Bjarke
    Fischer, Krista
    Frau, Francesca
    Galesloot, Tessel E
    Geller, Frank
    Goel, Anuj
    Gorski, Mathias
    Grammer, Tanja B
    Gustafsson, Stefan
    Haitjema, Saskia
    Hottenga, Jouke-Jan
    Huffman, Jennifer E
    Jackson, Anne U
    Jacobs, Kevin B
    Johansson, Åsa
    Kaakinen, Marika
    Kleber, Marcus E
    Lahti, Jari
    Mateo Leach, Irene
    Lehne, Benjamin
    Liu, Youfang
    Lo, Ken Sin
    Lorentzon, Mattias
    Luan, Jian'an
    Madden, Pamela A F
    Mangino, Massimo
    McKnight, Barbara
    Medina-Gomez, Carolina
    Monda, Keri L
    Montasser, May E
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Nolte, Ilja M
    Panoutsopoulou, Kalliope
    Pascoe, Laura
    Paternoster, Lavinia
    Rayner, Nigel W
    Renström, Frida
    Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
    Rizzi, Federica
    Rose, Lynda M
    Ryan, Kathy A
    Salo, Perttu
    Sanna, Serena
    Scharnagl, Hubert
    Shi, Jianxin
    Smith, Albert Vernon
    Southam, Lorraine
    Stančáková, Alena
    Steinthorsdottir, Valgerdur
    Strawbridge, Rona J
    Sung, Yun Ju
    Tachmazidou, Ioanna
    Tanaka, Toshiko
    Thorleifsson, Gudmar
    Trompet, Stella
    Pervjakova, Natalia
    Tyrer, Jonathan P
    Vandenput, Liesbeth
    van der Laan, Sander W
    van der Velde, Nathalie
    van Setten, Jessica
    van Vliet-Ostaptchouk, Jana V
    Verweij, Niek
    Vlachopoulou, Efthymia
    Waite, Lindsay L
    Wang, Sophie R
    Wang, Zhaoming
    Wild, Sarah H
    Willenborg, Christina
    Wilson, James F
    Wong, Andrew
    Yang, Jian
    Yengo, Loïc
    Yerges-Armstrong, Laura M
    Yu, Lei
    Zhang, Weihua
    Zhao, Jing Hua
    Andersson, Ehm A
    Bakker, Stephan J L
    Baldassarre, Damiano
    Banasik, Karina
    Barcella, Matteo
    Barlassina, Cristina
    Bellis, Claire
    Benaglio, Paola
    Blangero, John
    Blüher, Matthias
    Bonnet, Fabrice
    Bonnycastle, Lori L
    Boyd, Heather A
    Bruinenberg, Marcel
    Buchman, Aron S
    Campbell, Harry
    Chen, Yii-Der Ida
    Chines, Peter S
    Claudi-Boehm, Simone
    Cole, John
    Collins, Francis S
    de Geus, Eco J C
    de Groot, Lisette C P G M
    Dimitriou, Maria
    Duan, Jubao
    Enroth, Stefan
    Eury, Elodie
    Farmaki, Aliki-Eleni
    Forouhi, Nita G
    Friedrich, Nele
    Gejman, Pablo V
    Gigante, Bruna
    Glorioso, Nicola
    Go, Alan S
    Gottesman, Omri
    Gräßler, Jürgen
    Grallert, Harald
    Grarup, Niels
    Gu, Yu-Mei
    Broer, Linda
    Ham, Annelies C
    Hansen, Torben
    Harris, Tamara B
    Hartman, Catharina A
    Hassinen, Maija
    Hastie, Nicholas
    Hattersley, Andrew T
    Heath, Andrew C
    Henders, Anjali K
    Hernandez, Dena
    Hillege, Hans
    Holmen, Oddgeir
    Hovingh, Kees G
    Hui, Jennie
    Husemoen, Lise L
    Hutri-Kähönen, Nina
    Hysi, Pirro G
    Illig, Thomas
    De Jager, Philip L
    Jalilzadeh, Shapour
    Jørgensen, Torben
    Jukema, J Wouter
    Juonala, Markus
    Kanoni, Stavroula
    Karaleftheri, Maria
    Khaw, Kay Tee
    Kinnunen, Leena
    Kittner, Steven J
    Koenig, Wolfgang
    Kolcic, Ivana
    Kovacs, Peter
    Krarup, Nikolaj T
    Kratzer, Wolfgang
    Krüger, Janine
    Kuh, Diana
    Kumari, Meena
    Kyriakou, Theodosios
    Langenberg, Claudia
    Lannfelt, Lars
    Lanzani, Chiara
    Lotay, Vaneet
    Launer, Lenore J
    Leander, Karin
    Lindström, Jaana
    Linneberg, Allan
    Liu, Yan-Ping
    Lobbens, Stéphane
    Luben, Robert
    Lyssenko, Valeriya
    Männistö, Satu
    Magnusson, Patrik K
    McArdle, Wendy L
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Montgomery, Grant W
    Morris, Andrew P
    Narisu, Narisu
    Nelis, Mari
    Ong, Ken K
    Palotie, Aarno
    Pérusse, Louis
    Pichler, Irene
    Pilia, Maria G
    Pouta, Anneli
    Rheinberger, Myriam
    Ribel-Madsen, Rasmus
    Richards, Marcus
    Rice, Kenneth M
    Rice, Treva K
    Rivolta, Carlo
    Salomaa, Veikko
    Sanders, Alan R
    Sarzynski, Mark A
    Scholtens, Salome
    Scott, Robert A
    Scott, William R
    Sebert, Sylvain
    Sengupta, Sebanti
    Sennblad, Bengt
    Seufferlein, Thomas
    Silveira, Angela
    Slagboom, P Eline
    Smit, Jan H
    Sparsø, Thomas H
    Stirrups, Kathleen
    Stolk, Ronald P
    Stringham, Heather M
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Tan, Sian-Tsung
    Thorand, Barbara
    Tönjes, Anke
    Tremblay, Angelo
    Tsafantakis, Emmanouil
    van der Most, Peter J
    Völker, Uwe
    Vohl, Marie-Claude
    Vonk, Judith M
    Waldenberger, Melanie
    Walker, Ryan W
    Wennauer, Roman
    Widén, Elisabeth
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wright, Alan F
    Zillikens, M Carola
    van Dijk, Suzanne C
    van Schoor, Natasja M
    Asselbergs, Folkert W
    de Bakker, Paul I W
    Beckmann, Jacques S
    Beilby, John
    Bennett, David A
    Bergman, Richard N
    Bergmann, Sven
    Böger, Carsten A
    Boehm, Bernhard O
    Boerwinkle, Eric
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Chambers, John C
    Chanock, Stephen J
    Chasman, Daniel I
    Cucca, Francesco
    Cusi, Daniele
    Dedoussis, George
    Erdmann, Jeanette
    Eriksson, Johan G
    Evans, Denis A
    de Faire, Ulf
    Farrall, Martin
    Ferrucci, Luigi
    Ford, Ian
    Franke, Lude
    Franks, Paul W
    Umeå University Hospital; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America .
    Froguel, Philippe
    Gansevoort, Ron T
    Gieger, Christian
    Grönberg, Henrik
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hall, Per
    Hamsten, Anders
    van der Harst, Pim
    Hayward, Caroline
    Heliövaara, Markku
    Hengstenberg, Christian
    Hicks, Andrew A
    Hingorani, Aroon
    Hofman, Albert
    Hu, Frank
    Huikuri, Heikki V
    Hveem, Kristian
    James, Alan L
    Jordan, Joanne M
    Jula, Antti
    Kähönen, Mika
    Kajantie, Eero
    Kathiresan, Sekar
    Kiemeney, Lambertus A L M
    Kivimaki, Mika
    Knekt, Paul B
    Koistinen, Heikki A
    Kooner, Jaspal S
    Koskinen, Seppo
    Kuusisto, Johanna
    Maerz, Winfried
    Martin, Nicholas G
    Laakso, Markku
    Lakka, Timo A
    Lehtimäki, Terho
    Lettre, Guillaume
    Levinson, Douglas F
    Lind, Lars
    Lokki, Marja-Liisa
    Mäntyselkä, Pekka
    Melbye, Mads
    Metspalu, Andres
    Mitchell, Braxton D
    Moll, Frans L
    Murray, Jeffrey C
    Musk, Arthur W
    Nieminen, Markku S
    Njølstad, Inger
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Oostra, Ben A
    Palmer, Lyle J
    Pankow, James S
    Pasterkamp, Gerard
    Pedersen, Nancy L
    Pedersen, Oluf
    Penninx, Brenda W
    Perola, Markus
    Peters, Annette
    Polašek, Ozren
    Pramstaller, Peter P
    Psaty, Bruce M
    Qi, Lu
    Quertermous, Thomas
    Raitakari, Olli T
    Rankinen, Tuomo
    Rauramaa, Rainer
    Ridker, Paul M
    Rioux, John D
    Rivadeneira, Fernando
    Rotter, Jerome I
    Rudan, Igor
    den Ruijter, Hester M
    Saltevo, Juha
    Sattar, Naveed
    Schunkert, Heribert
    Schwarz, Peter E H
    Shuldiner, Alan R
    Sinisalo, Juha
    Snieder, Harold
    Sørensen, Thorkild I A
    Spector, Tim D
    Staessen, Jan A
    Stefania, Bandinelli
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tardif, Jean-Claude
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    Verbeek, André L M
    Vermeulen, Sita H
    Viikari, Jorma S
    Vitart, Veronique
    Völzke, Henry
    Vollenweider, Peter
    Waeber, Gérard
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Zeggini, Eleftheria
    Chakravarti, Aravinda
    Clegg, Deborah J
    Cupples, L Adrienne
    Gordon-Larsen, Penny
    Jaquish, Cashell E
    Rao, D C
    Abecasis, Goncalo R
    Assimes, Themistocles L
    Barroso, Inês
    Berndt, Sonja I
    Boehnke, Michael
    Deloukas, Panos
    Fox, Caroline S
    Groop, Leif C
    Hunter, David J
    Ingelsson, Erik
    Kaplan, Robert C
    McCarthy, Mark I
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Hirschhorn, Joel N
    Lindgren, Cecilia M
    Heid, Iris M
    North, Kari E
    Borecki, Ingrid B
    Kutalik, Zoltán
    Loos, Ruth J F
    The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study2015Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, nr 10, artikkel-id e1005378Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

  • 1063.
    Wirth, T
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Baur A, Baur B
    Mating system and genetic variability in the simultaneously hermaphroditic terrestrial gastropod Balea perversa on the Baltic island of Öland, Sweden.1997Inngår i: Hereditas, Vol. 126, s. 199-209Artikkel i tidsskrift (Fagfellevurdert)
  • 1064.
    Wisten, Aase
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Boström, Ida Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mörner, Stellan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mutation analysis of cases of sudden unexplained death, 15 years after death: Prompt genetic evaluation after resuscitation can save future lives2012Inngår i: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 83, nr 10, s. 1229-1234Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: The aim of this study is to use genetic mutation analysis to determine the cause of sudden unexpected death in young (SUDY) persons with normal autopsy findings, and to provide relatives with an identified cardiac mutation with suitable cardiovascular prevention. Methods: We performed mutation analysis on blood samples from first-degree relatives of 25 cases with normal autopsy findings identified in the national Swedish study of sudden cardiac death in 15- to 35-year-olds from 1992 to 1999. Results: We found three families with long QT syndrome through mutation screening, and the mutations were verified in two of the deceased. Eight family members were found to be mutation carriers and have been provided with suitable cardiovascular prevention. Mutation screening also identified a number of common polymorphisms in the individuals screened. Clinical history revealed one family each with short QT syndrome and hypertrophic cardiomyopathy, respectively, but no mutations were found in the family members or in the deceased. Two SCDs each had occurred in two of the affected families. Conclusion: Cardiac/genetic evaluation of relatives long after SUDY can reveal a diagnosis in 5/25 (20%) of cases. Since DNA extraction of formalin fixed paraffin embedded samples is unreliable, it is important that blood or tissue samples be stored at autopsy of such cases. This can facilitate establishing a diagnosis and thereby save lives in the future. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 1065. Wolff, Katharina
    et al.
    Nordin, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Vårdvetenskap.
    Brun, Wibecke
    Berglund, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Vårdvetenskap.
    Kvale, Gerd
    Affective and cognitive attitudes, uncertainty avoidance and intention to obtain genetic testing: An extension of the Theory of Planned Behaviour2011Inngår i: Psychology and Health, ISSN 0887-0446, E-ISSN 1476-8321, Vol. 26, nr 9, s. 1143-1155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To ensure successful implementation of genetic screening and counselling according to patients best interests, the attitudes and motives of the public are important to consider. The aim of this study was to apply a theoretical framework in order to investigate which individual and disease characteristics might facilitate the uptake of genetic testing. A questionnaire using an extended version of the Theory of Planned Behaviour was developed to assess the predictive value of affective and cognitive expected outcomes, subjective norms, perceived control and uncertainty avoidance on the intention to undergo genetic testing. In addition to these individual characteristics, the predictive power of two disease characteristics was investigated by systematically varying the diseases fatality and penetrance (i.e. the probability of getting ill in case one is a mutation carrier). This resulted in four versions of the questionnaire which was mailed to a random sample of 2400 Norwegians. Results showed genetic test interest to be quite high, and to vary depending on the characteristics of the disease, with participants preferring tests for highly penetrant diseases. The most important individual predictor was uncertainty avoidance.

  • 1066. Wolpin, Brian M.
    et al.
    Rizzato, Cosmeri
    Kraft, Peter
    Kooperberg, Charles
    Petersen, Gloria M.
    Wang, Zhaoming
    Arslan, Alan A.
    Beane-Freeman, Laura
    Bracci, Paige M.
    Buring, Julie
    Canzian, Federico
    Duell, Eric J.
    Gallinger, Steven
    Giles, Graham G.
    Goodman, Gary E.
    Goodman, Phyllis J.
    Jacobs, Eric J.
    Kamineni, Aruna
    Klein, Alison P.
    Kolonel, Laurence N.
    Kulke, Matthew H.
    Li, Donghui
    Malats, Nuria
    Olson, Sara H.
    Risch, Harvey A.
    Sesso, Howard D.
    Visvanathan, Kala
    White, Emily
    Zheng, Wei
    Abnet, Christian C.
    Albanes, Demetrius
    Andreotti, Gabriella
    Austin, Melissa A.
    Barfield, Richard
    Basso, Daniela
    Berndt, Sonja I.
    Boutron-Ruault, Marie-Christine
    Brotzman, Michelle
    Buechler, Markus W.
    Bueno-de-Mesquita, H. Bas
    Bugert, Peter
    Burdette, Laurie
    Campa, Daniele
    Caporaso, Neil E.
    Capurso, Gabriele
    Chung, Charles
    Cotterchio, Michelle
    Costello, Eithne
    Elena, Joanne
    Funel, Niccola
    Gaziano, J. Michael
    Giese, Nathalia A.
    Goggins, Michael
    Gorman, Megan J.
    Gross, Myron
    Haiman, Christopher A.
    Hassan, Manal
    Helzlsouer, Kathy J.
    Henderson, Brian E.
    Holly, Elizabeth A.
    Hu, Nan
    Hunter, David J.
    Innocenti, Federico
    Jenab, Mazda
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay-Tee
    Klein, Eric A.
    Kogevinas, Manolis
    Krogh, Vittorio
    Kupcinskas, Juozas
    Kurtz, Robert C.
    LaCroix, Andrea
    Landi, Maria T.
    Landi, Stefano
    Le Marchand, Loic
    Mambrini, Andrea
    Mannisto, Satu
    Milne, Roger L.
    Nakamura, Yusuke
    Oberg, Ann L.
    Owzar, Kouros
    Patel, Alpa V.
    Peeters, Petra H. M.
    Peters, Ulrike
    Pezzilli, Raffaele
    Piepoli, Ada
    Porta, Miquel
    Real, Francisco X.
    Riboli, Elio
    Rothman, Nathaniel
    Scarpa, Aldo
    Shu, Xiao-Ou
    Silverman, Debra T.
    Soucek, Pavel
    Sund, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap.
    Talar-Wojnarowska, Renata
    Taylor, Philip R.
    Theodoropoulos, George E.
    Thornquist, Mark
    Tjonneland, Anne
    Tobias, Geoffrey S.
    Trichopoulos, Dimitrios
    Vodicka, Pavel
    Wactawski-Wende, Jean
    Wentzensen, Nicolas
    Wu, Chen
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Hoover, Robert
    Hartge, Patricia
    Fuchs, Charles
    Chanock, Stephen J.
    Stolzenberg-Solomon, Rachael S.
    Amundadottir, Laufey T.
    Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 9, s. 994-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

  • 1067. Woltmann, Andrea
    et al.
    Chen, Bowang
    Lascorz, Jesus
    Johansson, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Eyfjord, Jorunn E.
    Hamann, Ute
    Manjer, Jonas
    Enquist-Olsson, Kerstin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Herms, Stefan
    Hoffmann, Per
    Hemminki, Kari
    Lenner, Per
    Forsti, Asta
    Systematic Pathway Enrichment Analysis of a Genome-Wide Association Study on Breast Cancer Survival Reveals an Influence of Genes Involved in Cell Adhesion and Calcium Signaling on the Patients' Clinical Outcome2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 6, s. e98229-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies (GWASs) may help to understand the effects of genetic polymorphisms on breast cancer (BC) progression and survival. However, they give only a focused view, which cannot capture the tremendous complexity of this disease. Therefore, we investigated data from a previously conducted GWAS on BC survival for enriched pathways by different enrichment analysis tools using the two main annotation databases Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The goal was to identify the functional categories (GO terms and KEGG pathways) that are consistently overrepresented in a statistically significant way in the list of genes generated from the single nucleotide polymorphism (SNP) data. The SNPs with allelic p-value cut-offs 0.005 and 0.01 were annotated to the genes by excluding or including a 20 kb up-and down-stream sequence of the genes and analyzed by six different tools. We identified eleven consistently enriched categories, the most significant ones relating to cell adhesion and calcium ion binding. Moreover, we investigated the similarity between our GWAS and the enrichment analyses of twelve published gene expression signatures for breast cancer prognosis. Five of them were commonly used and commercially available, five were based on different aspects of metastasis formation and two were developed from meta-analyses of published prognostic signatures. This comparison revealed similarities between our GWAS data and the general and the specific brain metastasis gene signatures as well as the Oncotype DX signature. As metastasis formation is a strong indicator of a patient's prognosis, this result reflects the survival aspect of the conducted GWAS and supports cell adhesion and calcium signaling as important pathways in cancer progression.

  • 1068. Wood, Andrew R
    et al.
    Esko, Tonu
    Yang, Jian
    Vedantam, Sailaja
    Pers, Tune H
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chu, Audrey Y
    Estrada, Karol
    Luan, Jian'an
    Kutalik, Zoltán
    Amin, Najaf
    Buchkovich, Martin L
    Croteau-Chonka, Damien C
    Day, Felix R
    Duan, Yanan
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fehrmann, Rudolf
    Ferreira, Teresa
    Jackson, Anne U
    Karjalainen, Juha
    Lo, Ken Sin
    Locke, Adam E
    Mägi, Reedik
    Mihailov, Evelin
    Porcu, Eleonora
    Randall, Joshua C
    Scherag, André
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Winkler, Thomas W
    Workalemahu, Tsegaselassie
    Zhao, Jing Hua
    Absher, Devin
    Albrecht, Eva
    Anderson, Denise
    Baron, Jeffrey
    Beekman, Marian
    Demirkan, Ayse
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Fraser, Ross M
    Goel, Anuj
    Gong, Jian
    Justice, Anne E
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Lui, Julian C
    Mangino, Massimo
    Leach, Irene Mateo
    Medina-Gomez, Carolina
    Nalls, Michael A
    Nyholt, Dale R
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Prokopenko, Inga
    Ried, Janina S
    Ripke, Stephan
    Shungin, Dmitry
    Stancáková, Alena
    Strawbridge, Rona J
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Afzal, Uzma
    Arnlöv, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Arscott, Gillian M
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Blüher, Matthias
    Bolton, Jennifer L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Buckley, Brendan M
    Buyske, Steven
    Caspersen, Ida H
    Chines, Peter S
    Clarke, Robert
    Claudi-Boehm, Simone
    Cooper, Matthew
    Daw, E Warwick
    De Jong, Pim A
    Deelen, Joris
    Delgado, Graciela
    Denny, Josh C
    Dhonukshe-Rutten, Rosalie
    Dimitriou, Maria
    Doney, Alex S F
    Dörr, Marcus
    Eklund, Niina
    Eury, Elodie
    Folkersen, Lasse
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Go, Alan S
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    de Groot, Lisette C P G M
    Groves, Christopher J
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Goran
    Hannemann, Anke
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hemani, Gibran
    Henders, Anjali K
    Hillege, Hans L
    Hlatky, Mark A
    Hoffmann, Wolfgang
    Hoffmann, Per
    Holmen, Oddgeir
    Houwing-Duistermaat, Jeanine J
    Illig, Thomas
    Isaacs, Aaron
    James, Alan L
    Jeff, Janina
    Johansen, Berit
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Junttila, Juhani
    Kho, Abel N
    Kinnunen, Leena
    Klopp, Norman
    Kocher, Thomas
    Kratzer, Wolfgang
    Lichtner, Peter
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindström, Jaana
    Lobbens, Stéphane
    Lorentzon, Mattias
    Lu, Yingchang
    Lyssenko, Valeriya
    Magnusson, Patrik K E
    Mahajan, Anubha
    Maillard, Marc
    McArdle, Wendy L
    McKenzie, Colin A
    McLachlan, Stela
    McLaren, Paul J
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Narisu, Narisu
    Nauck, Matthias
    Nolte, Ilja M
    Nöthen, Markus M
    Oozageer, Laticia
    Pilz, Stefan
    Rayner, Nigel W
    Renstrom, Frida
    Robertson, Neil R
    Rose, Lynda M
    Roussel, Ronan
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Schunkert, Heribert
    Scott, Robert A
    Sehmi, Joban
    Seufferlein, Thomas
    Shi, Jianxin
    Silventoinen, Karri
    Smit, Johannes H
    Smith, Albert Vernon
    Smolonska, Joanna
    Stanton, Alice V
    Stirrups, Kathleen
    Stott, David J
    Stringham, Heather M
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Swertz, Morris A
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tayo, Bamidele O
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    van Dijk, Suzanne
    van Schoor, Natasja M
    van der Velde, Nathalie
    van Heemst, Diana
    van Oort, Floor V A
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Waldenberger, Melanie
    Wennauer, Roman
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Biffar, Reiner
    Blangero, John
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bovet, Pascal
    Brambilla, Paolo
    Brown, Morris J
    Campbell, Harry
    Caulfield, Mark J
    Chakravarti, Aravinda
    Collins, Rory
    Collins, Francis S
    Crawford, Dana C
    Cupples, L Adrienne
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Golay, Alain
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haas, David W
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Heath, Andrew C
    Hengstenberg, Christian
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Hovingh, G Kees
    Humphries, Steve E
    Hunt, Steven C
    Hypponen, Elina
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jousilahti, Pekka
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Kayser, Manfred
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Kooner, Jaspal S
    Kooperberg, Charles
    Koskinen, Seppo
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lupoli, Sara
    Madden, Pamela A F
    Männistö, Satu
    Manunta, Paolo
    Marette, André
    Matise, Tara C
    McKnight, Barbara
    Meitinger, Thomas
    Moll, Frans L
    Montgomery, Grant W
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Ouwehand, Willem H
    Pasterkamp, Gerard
    Peters, Annette
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ritchie, Marylyn
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schwarz, Peter E H
    Sebert, Sylvain
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P
    Tardif, Jean-Claude
    Tönjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hayes, M Geoffrey
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Jukema, J Wouter
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Powell, Joseph E
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Reinmaa, Eva
    Ridker, Paul M
    Rivadeneira, Fernando
    Rotter, Jerome I
    Saaristo, Timo E
    Saleheen, Danish
    Schlessinger, David
    Slagboom, P Eline
    Snieder, Harold
    Spector, Tim D
    Strauch, Konstantin
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van der Harst, Pim
    Völzke, Henry
    Walker, Mark
    Wareham, Nicholas J
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Deloukas, Panos
    Heid, Iris M
    Lindgren, Cecilia M
    Mohlke, Karen L
    Speliotes, Elizabeth K
    Thorsteinsdottir, Unnur
    Barroso, Inês
    Fox, Caroline S
    North, Kari E
    Strachan, David P
    Beckmann, Jacques S
    Berndt, Sonja I
    Boehnke, Michael
    Borecki, Ingrid B
    McCarthy, Mark I
    Metspalu, Andres
    Stefansson, Kari
    Uitterlinden, André G
    van Duijn, Cornelia M
    Franke, Lude
    Willer, Cristen J
    Price, Alkes L
    Lettre, Guillaume
    Loos, Ruth J F
    Weedon, Michael N
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    O'Connell, Jeffrey R
    Abecasis, Goncalo R
    Chasman, Daniel I
    Goddard, Michael E
    Visscher, Peter M
    Hirschhorn, Joel N
    Frayling, Timothy M
    Defining the role of common variation in the genomic and biological architecture of adult human height2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 11, s. 1173-1186Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

  • 1069. Wood, Andrew R
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    Esko, Tonu
    Yang, Jian
    Vedantam, Sailaja
    Pers, Tune H
    Gustafsson, Stefan
    Chu, Audrey Y
    Estrada, Karol
    Luan, Jian'an
    Kutalik, Zoltán
    Amin, Najaf
    Buchkovich, Martin L
    Croteau-Chonka, Damien C
    Day, Felix R
    Duan, Yanan
    Fall, Tove
    Fehrmann, Rudolf
    Ferreira, Teresa
    Jackson, Anne U
    Karjalainen, Juha
    Lo, Ken Sin
    Locke, Adam E
    Mägi, Reedik
    Mihailov, Evelin
    Porcu, Eleonora
    Randall, Joshua C
    Scherag, André
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Winkler, Thomas W
    Workalemahu, Tsegaselassie
    Zhao, Jing Hua
    Absher, Devin
    Albrecht, Eva
    Anderson, Denise
    Baron, Jeffrey
    Beekman, Marian
    Demirkan, Ayse
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Fraser, Ross M
    Goel, Anuj
    Gong, Jian
    Justice, Anne E
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Lui, Julian C
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Nalls, Michael A
    Nyholt, Dale R
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Prokopenko, Inga
    Ried, Janina S
    Ripke, Stephan
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Stancáková, Alena
    Strawbridge, Rona J
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Afzal, Uzma
    Arnlöv, Johan
    Arscott, Gillian M
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Blüher, Matthias
    Bolton, Jennifer L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Buckley, Brendan M
    Buyske, Steven
    Caspersen, Ida H
    Chines, Peter S
    Clarke, Robert
    Claudi-Boehm, Simone
    Cooper, Matthew
    Daw, E Warwick
    De Jong, Pim A
    Deelen, Joris
    Delgado, Graciela
    Denny, Josh C
    Dhonukshe-Rutten, Rosalie
    Dimitriou, Maria
    Doney, Alex S F
    Dörr, Marcus
    Eklund, Niina
    Eury, Elodie
    Folkersen, Lasse
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Go, Alan S
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    de Groot, Lisette C P G M
    Groves, Christopher J
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hannemann, Anke
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hemani, Gibran
    Henders, Anjali K
    Hillege, Hans L
    Hlatky, Mark A
    Hoffmann, Wolfgang
    Hoffmann, Per
    Holmen, Oddgeir
    Houwing-Duistermaat, Jeanine J
    Illig, Thomas
    Isaacs, Aaron
    James, Alan L
    Jeff, Janina
    Johansen, Berit
    Johansson, Asa
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Junttila, Juhani
    Kho, Abel N
    Kinnunen, Leena
    Klopp, Norman
    Kocher, Thomas
    Kratzer, Wolfgang
    Lichtner, Peter
    Lind, Lars
    Lindström, Jaana
    Lobbens, Stéphane
    Lorentzon, Mattias
    Lu, Yingchang
    Lyssenko, Valeriya
    Magnusson, Patrik K E
    Mahajan, Anubha
    Maillard, Marc
    McArdle, Wendy L
    McKenzie, Colin A
    McLachlan, Stela
    McLaren, Paul J
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Narisu, Narisu
    Nauck, Matthias
    Nolte, Ilja M
    Nöthen, Markus M
    Oozageer, Laticia
    Pilz, Stefan
    Rayner, Nigel W
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Robertson, Neil R
    Rose, Lynda M
    Roussel, Ronan
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Schunkert, Heribert
    Scott, Robert A
    Sehmi, Joban
    Seufferlein, Thomas
    Shi, Jianxin
    Silventoinen, Karri
    Smit, Johannes H
    Smith, Albert Vernon
    Smolonska, Joanna
    Stanton, Alice V
    Stirrups, Kathleen
    Stott, David J
    Stringham, Heather M
    Sundström, Johan
    Swertz, Morris A
    Syvänen, Ann-Christine
    Tayo, Bamidele O
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    van Dijk, Suzanne
    van Schoor, Natasja M
    van der Velde, Nathalie
    van Heemst, Diana
    van Oort, Floor V A
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Waldenberger, Melanie
    Wennauer, Roman
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Biffar, Reiner
    Blangero, John
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bovet, Pascal
    Brambilla, Paolo
    Brown, Morris J
    Campbell, Harry
    Caulfield, Mark J
    Chakravarti, Aravinda
    Collins, Rory
    Collins, Francis S
    Crawford, Dana C
    Cupples, L Adrienne
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Golay, Alain
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Haas, David W
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Heath, Andrew C
    Hengstenberg, Christian
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Hovingh, G Kees
    Humphries, Steve E
    Hunt, Steven C
    Hypponen, Elina
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jousilahti, Pekka
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Kayser, Manfred
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Kooner, Jaspal S
    Kooperberg, Charles
    Koskinen, Seppo
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lupoli, Sara
    Madden, Pamela A F
    Männistö, Satu
    Manunta, Paolo
    Marette, André
    Matise, Tara C
    McKnight, Barbara
    Meitinger, Thomas
    Moll, Frans L
    Montgomery, Grant W
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Ouwehand, Willem H
    Pasterkamp, Gerard
    Peters, Annette
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ritchie, Marylyn
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schwarz, Peter E H
    Sebert, Sylvain
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P
    Tardif, Jean-Claude
    Tönjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hayes, M Geoffrey
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Jukema, J Wouter
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Powell, Joseph E
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Reinmaa, Eva
    Ridker, Paul M
    Rivadeneira, Fernando
    Rotter, Jerome I
    Saaristo, Timo E
    Saleheen, Danish
    Schlessinger, David
    Slagboom, P Eline
    Snieder, Harold
    Spector, Tim D
    Strauch, Konstantin
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van der Harst, Pim
    Völzke, Henry
    Walker, Mark
    Wareham, Nicholas J
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Deloukas, Panos
    Heid, Iris M
    Lindgren, Cecilia M
    Mohlke, Karen L
    Speliotes, Elizabeth K
    Thorsteinsdottir, Unnur
    Barroso, Inês
    Fox, Caroline S
    North, Kari E
    Strachan, David P
    Beckmann, Jacques S
    Berndt, Sonja I
    Boehnke, Michael
    Borecki, Ingrid B
    McCarthy, Mark I
    Metspalu, Andres
    Stefansson, Kari
    Uitterlinden, André G
    van Duijn, Cornelia M
    Franke, Lude
    Willer, Cristen J
    Price, Alkes L
    Lettre, Guillaume
    Loos, Ruth J F
    Weedon, Michael N
    Ingelsson, Erik
    O'Connell, Jeffrey R
    Abecasis, Goncalo R
    Chasman, Daniel I
    Goddard, Michael E
    Visscher, Peter M
    Hirschhorn, Joel N
    Frayling, Timothy M
    Defining the role of common variation in the genomic and biological architecture of adult human height2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 11, s. 1173-1186Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

  • 1070. Wright, Alison E.
    et al.
    Darolti, Iulia
    Bloch, Natasha I.
    Oostra, Vicencio
    Sandkam, Ben
    Buechel, Severine D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kolm, Niclas
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Breden, Felix
    Vicoso, Beatriz
    Mank, Judith E.
    Convergent recombination suppression suggests role of sexual selection in guppy sex chromosome formation2017Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 14251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex chromosomes evolve once recombination is halted between a homologous pair of chromosomes. The dominant model of sex chromosome evolution posits that recombination is suppressed between emerging X and Y chromosomes in order to resolve sexual conflict. Here we test this model using whole genome and transcriptome resequencing data in the guppy, a model for sexual selection with many Y-linked colour traits. We show that although the nascent Y chromosome encompasses nearly half of the linkage group, there has been no perceptible degradation of Y chromosome gene content or activity. Using replicate wild populations with differing levels of sexually antagonistic selection for colour, we also show that sexual selection leads to greater expansion of the non-recombining region and increased Y chromosome divergence. These results provide empirical support for longstanding models of sex chromosome catalysis, and suggest an important role for sexual selection and sexual conflict in genome evolution.

  • 1071.
    Wu, Cuiyan
    et al.
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Liu, Huan
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Zhang, Feng'e
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Shao, Wanzhen
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Yang, Lei
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Ning, Yujie
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Wang, Sen
    School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission of the People's Republic of China, Xi'an, P.R. China.
    Zhao, Guanghui
    Department of Knee Joint, Xi'an Hong Hui Hospital, Xi'an, P.R. China.
    Lee, Byeong Jae
    Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, Korea.
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Guo, Xiong
    Long noncoding RNA expression profile reveals lncRNAs signature associated with extracellular matrix degradation in kashin-beck disease2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 17553Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kashin-Beck disease (KBD) is a deformative, endemic osteochondropathy involving degeneration and necrosis of growth plates and articular cartilage. The pathogenesis of KBD is related to gene expression and regulation mechanisms, but long noncoding RNAs (lncRNAs) in KBD have not been investigated. In this study, we identified 316 up-regulated and 631 down-regulated lncRNAs (≥ 2-fold change) in KBD chondrocytes using microarray analysis, of which more than three-quarters were intergenic lncRNAs and antisense lncRNAs. We also identified 232 up-regulated and 427 down-regulated mRNAs (≥ 2-fold change). A lncRNA-mRNA correlation analysis combined 343 lncRNAs and 292 mRNAs to form 509 coding-noncoding gene co-expression networks (CNC networks). Eleven lncRNAs were predicted to have cis-regulated target genes, including NAV2 (neuron navigator 2), TOX (thymocyte selection-associated high mobility group box), LAMA4 (laminin, alpha 4), and DEPTOR (DEP domain containing mTOR-interacting protein). The differentially expressed mRNAs in KBD significantly contribute to biological events associated with the extracellular matrix. Meanwhile, 34 mRNAs and 55 co-expressed lncRNAs constituted a network that influences the extracellular matrix. In the network, FBLN1 and LAMA 4 were the core genes with the highest significance. These novel findings indicate that lncRNAs may play a role in extracellular matrix destruction in KBD.

  • 1072.
    Wu, Siqin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    The Myc network of growth regulators and its interplay with growth and differentiation signals2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The proto-oncogenes/tumor suppressor genes of the Myc/N4ax/Mad network encode transcription factors that are important regulators of cell growth, differentiation, and apoptosis and that are frequently implicated in tumor development. Regulation of their biological functions by growth/differentiation signals as well as their interplay with growth/differentiation signalling pathways play important roles in cell fate determination. Elucidation of the underlying mechanisms, an issue addressed in this thesis, may not only increase our basic knowledge about eukaryotic growth regulation but may also contribute to novel therapeutic strategies for treatment of cancer.

    Deregulated Myc expression blocks differentiation and anti-proliferative signals in a number of experimental systems. However, interferon-γ (IFN-γ) was shown to restore induced terminal differentiation of v-Myc-transformed U-937 human monoblasts. This thesis shows that several other cytokines, including interieukin-6 (IL-6), granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming growth factor β (TGF-β), also restore phorbol ester (TPA)-induced growth arrest and/or differentiation of these cells, despite continuous expression of v-Myc. Addressing the mechanism(s) behind the cytokine-induced anti-Myc activity, the thesis shows that TPA+IFN-γ treatment inhibits Myc-induced transcription and Mye DNA binding activity. This occurs through destabilisation of Myc's interaction with its essential partner Max, a mechanism correlated with post-translational modification of Myc by dephosphorylation. TGFβ treatment, in contrast, leads to up-regulation of the Myc antagonist, Mad1. The upregulation of Mad1 is correlated to increased Madl/Max complex formation and repression of Myc-dependent transcription.

    The thesis further shows that Myc not only interferes with differentiation signals by activating target genes but also by repressing transcription of the cyclin-dependent kinase inhibitor p2lCIPl, a key regulator of the cell cycle, through a control region close to the transcriptional start site.

    In conclusion, the thesis suggests that cytokine-induced signals can inhibit Myc function through direct posttranslational modification of Myc or alternatively through upregulation of its antagonist Mad1. On the other hand, Myc also interferes with differentiation signals by repressing inhibitors of cell cycle progression.

  • 1073. Xochelli, Aliki
    et al.
    Agathangelidis, Andreas
    Kavakiotis, Ioannis
    Minga, Evangelia
    Sutton, Lesley Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chouvarda, Ioanna
    Giudicelli, Veronique
    Vlahavas, Ioannis
    Maglaveras, Nikos
    Bonello, Lisa
    Trentin, Livio
    Tedeschi, Alessandra
    Panagiotidis, Panagiotis
    Geisler, Christian
    Langerak, Anton W.
    Pospisilova, Sarka
    Jelinek, Diane F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Oscier, David
    Chiorazzi, Nicholas
    Darzentas, Nikos
    Davi, Fred
    Ghia, Paolo
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hadzidimitriou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Belessi, Chrysoula
    Lefranc, Marie-Paule
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia2015Inngår i: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 67, nr 1, s. 61-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ieext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.

  • 1074. Xochelli, Aliki
    et al.
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moore, Sarah
    Sole, Francesc
    Wickham, Nicholas
    Salido, Marta
    Athanasiadou, Anastasia
    Oscier, David
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Trans location t(2;7)(p11.2;q21.2): a rare genetic aberration associated with B-cell lymphoproliferative disorders of marginal-zone origin2014Inngår i: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 207, nr 6, s. 281-283Artikkel i tidsskrift (Fagfellevurdert)
  • 1075.
    Yamamoto, Toshiyuki
    et al.
    Tokyo Womens Medical University, Japan .
    Wilsdon, Anna
    Nottingham City Hospital, UK.
    Joss, Shelagh
    Southern General Hospital, Glasgow, UK.
    Isidor, Bertrand
    Centre Hospital University of Nantes 7, France Institute Thorax, France .
    Erlandsson, Anna
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Suri, Mohnish
    Nottingham City Hospital, UK.
    Sangu, Noriko
    Tokyo Womens Medical University, Japan .
    Shimada, Shino
    Tokyo Womens Medical University, Japan .
    Shimojima, Keiko
    Tokyo Womens Medical University, Japan .
    Le Caignec, Cedric
    Centre Hospital University of Nantes 7, France Institute Thorax, France .
    Samuelsson, Lena
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Stefanova, Margarita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik. Sahlgrenska University Hospital, Gothenburg, Sweden.
    An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities2014Inngår i: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 59, nr 6, s. 300-306Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (greater than3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.

  • 1076.
    Yang, Fan
    et al.
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.;Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada..
    Sun, Song
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.;Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada..
    Tan, Guihong
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Costanzo, Michael
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Hill, David E.
    Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Vidal, Marc
    Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Andrews, Brenda J.
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Boone, Charles
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Canadian Inst Adv Res, Toronto, ON, Canada..
    Roth, Frederick P.
    Donnelly Ctr, Toronto, ON, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.;Univ Toronto, Dept Comp Sci, Toronto, ON, Canada.;Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada.;Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA.;Canadian Inst Adv Res, Toronto, ON, Canada..
    Identifying pathogenicity of human variants via paralog-based yeast complementation2017Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 5, artikkel-id e1006779Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97%) were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

  • 1077.
    Yang, Hai-Tao
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Genetic analysis of autoimmune diseases using animal models: Mapping susceptibility genes for multiple sclerosis and rheumatoid arthritis2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Autoimmune diseases such as rheumatoid arthritis and multiple sclerosis are common human diseasesaffecting 1% and 0.1% of the population respectively. These diseases are characterized by abnormal self-tolerance in the immune system and autoimmune reactions. Epidemiological studies indicate that geneticcomponents together with environmental factors influence these diseases.

    The etiology of autoimmune diseases is poorly understood. Previous studies have found that MHCgenes are important for disease but these studies also indicated that additional genes are involved.

    Studies of complex diseases such as autoimmune diseases are difficult because they are caused by more than one gene or the interactions between several genes along with environmental factors. Directanalysis of complex diseases in human families is often hampered by incomplete penetrance, phenocopies and genetic heterogeneity.

    Analysing complex diseases by using animal models provides a shortcut because environmental factors can be controlled and the populations are more homogenous. This thesis work has analysed several animal models for autoimmune diseases in mice and rats by genome-wide scans and multi-trait quantitative trait loci (QTL) linkage analysis. Experimental allergic encephalomyelitis (EAE) is an animal model for human MS and collagen induced arthritis (CIA) is a model for RA.

    We found a number of susceptiblility loci for EAE and CIA which mapped to different chromosomal regions. We mapped 3 non-MHC loci in the EAE mouse model. Also. 4 loci were mapped in the mouse CIA model and 11 loci in the EAE rat model. Among these susceptibile loci, we found that some of them are shared between EAE and arthritis and therefore may contain common autoimmune disease genes.

  • 1078.
    Yang, Jian
    et al.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia..
    Bakshi, Andrew
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Zhu, Zhihong
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Hemani, Gibran
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Bristol, Sch Social & Community Med, IEU, MRC, Bristol, Avon, England..
    Vinkhuyzen, Anna A. E.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Lee, Sang Hong
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ New England, Sch Environm & Rural Sci, Armidale, NSW, Australia..
    Robinson, Matthew R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Perry, John R. B.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol, Cambridge, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Soranzo, Nicole
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Keller, Matthew C.
    Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA.;Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA..
    Wray, Naomi R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Goddard, Michael E.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia.;Jobs Transport & Resources, Dept Econ Dev, Biosci Res Div, Bundoora, Vic, Australia..
    Visscher, Peter M.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld, Australia..
    Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 10, s. 1114-1120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that similar to 97% and similar to 68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all similar to 17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

  • 1079. Yang, Lei
    et al.
    Zhao, Guang-Hui
    Liu, Huan
    Wang, Xi
    Guo, Xiong
    Lammi, Mikko J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). School of Public Health, Health Science Center, Xi’an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi’an, People’s Republic of China.
    Field synopsis and meta-analyses of genetic epidemiological evidence for Kashin-Beck disease, an endemic osteoarthropathy in China2016Inngår i: Molecular Genetics and Genomics, ISSN 1617-4615, E-ISSN 1617-4623, Vol. 291, nr 5, s. 1823-1833, artikkel-id 27256326Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kashin-Beck disease (KBD) is a chronic degenerative osteoarthropathy with unclear etiology. To provide current evidence supporting a genetic predisposition for KBD, we conducted a systematic review and meta-analysis of published literature on the genetic epidemiology of KBD. The PubMed, China National Knowledge Infrastructure and Wan Fang Data were searched up to August 2015 for articles published in English and Chinese. Genome-wide and exome sequencing, linkage, and case-control association studies for any genetic variants associated with KBD were included. Meta-analysis was performed for all single nucleotide polymorphisms (SNPs) that were evaluated in two or more studies. The effect size was summarized as odds ratios (ORs) with 95 % confidence intervals (CIs) by fixed and random effects models. A total of 24 articles were systematically reviewed. Eleven short tandem repeats on chromosomes 2, 11 and 12, 34 SNPs in 12 genes, as well as copy number variant 452 were identified as KBD susceptibility factors in individual studies. The meta-analysis of the GPX1 rs1050450, DIO2 rs225014, TrxR2 rs5748469 and HLA-DRB1 rs7745040 failed to reveal any associations with KBD. However, the meta-analysis of HLA-DRB1 rs9275295 allele A was associated with KBD (OR = 1.737, 95 % CI: 1.002-3.012). In addition, seven haplotypes in GPX1, GPX4, HLA-DRB1 and GDF5 genes also showed significant associations with KBD. In conclusions, our study could identify a number of genetic markers associated with KBD. However, the evidence does not currently support a strong association between the specific variants and KBD because of the limited number of studies, and in the future, more rigorous studies are needed to confirm KBD's links with these variants.

  • 1080. Yoshida, Kazumasa
    et al.
    Bacal, Julien
    Desmarais, Damien
    Padioleau, Ismaël
    Tsaponina, Olga
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pantesco, Véronique
    Dubois, Emeric
    Parrinello, Hugues
    Skrzypczak, Magdalena
    Ginalski, Krzysztof
    Lengronne, Armelle
    Pasero, Philippe
    The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast2014Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 54, nr 4, s. 691-697Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In S. cerevisiae, replication timing is controlled by epigenetic mechanisms restricting the accessibility of origins to limiting initiation factors. About 30% of these origins are located within repetitive DNA sequences such as the ribosomal DNA (rDNA) array, but their regulation is poorly understood. Here, we have investigated how histone deacetylases (HDACs) control the replication program in budding yeast. This analysis revealed that two HDACs, Rpd3 and Sir2, control replication timing in an opposite manner. Whereas Rpd3 delays initiation at late origins, Sir2 is required for the timely activation of early origins. Moreover, Sir2 represses initiation at rDNA origins, whereas Rpd3 counteracts this effect. Remarkably, deletion of SIR2 restored normal replication in rpd3Δ cells by reactivating rDNA origins. Together, these data indicate that HDACs control the replication timing program in budding yeast by modulating the ability of repeated origins to compete with single-copy origins for limiting initiation factors.

  • 1081.
    Younis, Shady
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala University.
    Functional characterization of the biological significance of the ZBED6/ZC3H11A locus in placental mammals2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The recent advances in molecular and computational biology have made possible the study of complicated transcriptional regulatory networks that control a wide range of biological processes and phenotypic traits. In this thesis, several approaches were combined including next generation sequencing, gene expression profiling, chromatin and RNA immunoprecipitation, bioinformatics and genome editing methods in order to characterize the biological significance of the ZBED6 and ZC3H11A genes.

    A mutation in the binding site of ZBED6, located in an intron of IGF2, disrupts the binding and leads to 3-fold upregulation of IGF2 mRNA in pig muscle tissues. The first part of the thesis presents a detailed functional characterization of ZBED6. Transient silencing of ZBED6 expression in mouse myoblasts led to increased Igf2 expression (~2-fold). ChIP-seq analysis of ZBED6 and histone modifications showed that ZBED6 preferentially binds active promoters and modulates their transcriptional activities (paper I). In the follow-up studies using CRISPR/Cas9 we showed that either the deletion of ZBED6 or its binding site in Igf2 (Igf2ΔGGCT) led to more than 30-fold up-regulation of Igf2 expression in myoblasts. Differentiation of these genetically engineered cells resulted in hypertrophic myotubes. Transcriptome analysis revealed ~30% overlap between the differentially expressed genes in Zbed6-/- and Igf2ΔGGCT myotubes, with significant enrichment of muscle-specific genes. ZBED6-overexpression in myoblasts led to cell cycle arrest, reduced cell viability, reduced mitochondrial activities and impaired the differentiation of myoblasts (paper II). Further studies on cancer cells showed that ZBED6 influences the growth of colorectal cancer cells with dramatic changes in the transcription of hundreds of cancer-related genes (paper III). The phenotypic characterization of Zbed6-/- and Igf2pA/mG mouse models showed that the ZBED6-Igf2 axis has a major effect on regulating muscle growth and the growth of internal organs. Transcriptome analysis demonstrated a massive up-regulation of Igf2 expression (~30-fold) in adult tissues, but not in fetal tissues, of transgenic mice (paper IV).

    In the second part of the thesis we investigated the cellular function of Zc3h11a, the gene harboring ZBED6 in one of its first introns. The function of the ZC3H11A protein is so far poorly characterized. We show that ZC3H11A is a novel stress-induced protein that is required for efficient mRNA export from the nucleus. The inactivation of ZC3H11A inhibited the growth of multiple viruses including HIV, influenza, HSV and adenoviruses (paper V).

  • 1082.
    Younis, Shady
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Kamel, Wael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wang, Hao
    Department of Biochemistry and Biophysics, Stockholm University.
    Yu, Di
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Daniels, Robert
    Department of Biochemistry and Biophysics, Stockholm University.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hinkula, Jorma
    Department of Clinical and Experimental Medicine, Linköping University.
    Akusjärvi, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Andersson, Leif
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Multiple viruses rely on the stress-induced protein ZC3H11A for efficient replication2017Manuskript (preprint) (Annet vitenskapelig)
  • 1083. Yousefzadeh, M. J.
    et al.
    Wyatt, D. W.
    Takata, K.
    Mu, Y.
    Hensley, S. C.
    Tomida, J.
    Bylund, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doublie, S.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ramsden, D. A.
    McBride, K. M.
    Wood, R. D.
    Mammalian POLQ, Chromosome Stability and DNA Double-Strand Break Repair2015Inngår i: Environmental and Molecular Mutagenesis, ISSN 0893-6692, E-ISSN 1098-2280, Vol. 56, s. S48-S48Artikkel i tidsskrift (Annet vitenskapelig)
  • 1084. Yousefzadeh, Matthew J
    et al.
    Wyatt, David W
    Takata, Kei-Ichi
    Mu, Yunxiang
    Hensley, Sean C
    Tomida, Junya
    Bylund, Göran O
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doublié, Sylvie
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ramsden, Dale A
    McBride, Kevin M
    Wood, Richard D
    Mechanism of suppression of chromosomal instability by DNA polymerase POLQ2014Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, nr 10, s. e1004654-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.

  • 1085.
    Yu, N
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi.
    Fu, YX
    Sambuughin, N
    Ramsay, M
    Jenkins, T
    Leskinen, E
    Patthy, L
    Jorde, LB
    Kuromori, T
    Li, WH
    Global patterns of human DNA sequence variation in a 10-kb region on chromosome 12001Inngår i: MOLECULAR BIOLOGY AND EVOLUTION, Vol. 18, nr 2, s. 214-222Artikkel i tidsskrift (Fagfellevurdert)
  • 1086.
    Zaghlool, Ammar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Genome-wide Characterization of RNA Expression and Processing2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The production of fully mature protein-coding transcripts is an intricate process that involves numerous regulation steps. The complexity of these steps provides the means for multilayered control of gene expression. Comprehensive understanding of gene expression regulation is essential for interpreting the role of gene expression programs in tissue specificity, development and disease. In this thesis, we aim to provide a better global view of the human transcriptome, focusing on its content, synthesis, processing and regulation using next-generation sequencing as a read-out.

    In Paper I, we show that sequencing of total RNA provides unique insights into RNA processing. Our results revealed that co-transcriptional splicing is a widespread mechanism in human and chimpanzee brain tissues. We also found a correlation between slowly removed introns and alternative splicing. In Paper II, we explore the benefits of exome capture approaches in combination with RNA-sequencing to detect transcripts expressed at low-levels. Based on our results, we demonstrate that this approach increases the sensitivity for detecting low level transcripts and leads to the identification of novel exons and splice isoforms. In Paper III, we highlight the advantages of performing RNA-sequencing on separate cytoplasmic and nuclear RNA fractions. In comparison with conventional poly(A) RNA, cytoplasmic RNA contained a significantly higher fraction of exonic sequence, providing increased sensitivity for splice junction detection and for improved de novo assembly. Conversely, the nuclear fraction showed an enrichment of unprocessed RNA compared to when sequencing total RNA, making it suitable for analysis of RNA processing dynamics. In Paper IV, we used exome sequencing to sequence the DNA of a patient with unexplained intellectual disability and identified a de novo mutation in BAZ1A, which encodes the chromatin-remodeling factor ACF1. Functional studies indicated that the mutation influences the expression of genes involved in extracellular matrix organization, synaptic function and vitamin D3 metabolism. The differential expression of CYP24A, SYNGAP1 and COL1A2 correlated with the patient’s clinical diagnosis.

    The findings presented in this thesis contribute towards an improved understanding of the human transcriptome in health and disease, and highlight the advantages of developing novel methods to obtain global and comprehensive views of the transcriptome.

  • 1087.
    Zaghlool, Ammar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Splicing in the Human Brain2014Inngår i: Brain Transcriptome, Elsevier, 2014, s. 95-125Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    It has become increasingly clear over the past decade that RNA has important functions in human cells beyond its role as an intermediate translator of DNA to protein. It is now known that RNA plays highly specific roles in pathways involved in regulatory, structural, and catalytic functions. The complexity of RNA production and regulation has become evident with the advent of high-throughput methods to study the transcriptome. Deep sequencing has revealed an enormous diversity of RNA types and transcript isoforms in human cells. The transcriptome of the human brain is particularly interesting as it contains more expressed genes than other tissues and also displays an extreme diversity of transcript isoforms, indicating that highly complex regulatory pathways are present in the brain. Several of these regulatory proteins are now identified, including RNA-binding proteins that are neuron specific. RNA-binding proteins also play important roles in regulating the splicing process and the temporal and spatial isoform production. While significant progress has been made in understanding the human transcriptome, many questions still remain regarding the basic mechanisms of splicing and subcellular localization of RNA. A long-standing question is to what extent the splicing of pre-mRNA is cotranscriptional and posttranscriptional, respectively. Recent data, including studies of the human brain, indicate that splicing is primarily cotranscriptional in human cells. This chapter describes the current understanding of splicing and splicing regulation in the human brain and discusses the recent global sequence-based analyses of transcription and splicing.

  • 1088.
    Zainuddin, Norafiza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Molecular Genetic Analysis in B-cell Lymphomas: A Focus on the p53 Pathway and p16INK4a2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The presence of TP53 mutations has been associated with inferior outcome in diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). In DLBCL, the impact of the TP53 codon 72 polymorphism and MDM2 SNP309 has not been clearly elucidated, whereas MDM2 SNP309 was suggested as a poor-prognostic marker in CLL. In addition, p16INK4a promoter hypermethylation has been implicated as a negative prognostic factor in DLBCL. The aim of this thesis was to further evaluate these molecular markers in well-characterised materials of DLBCL and CLL.

    In paper I, we investigated the prognostic role of TP53 mutation, codon 72 polymorphism and MDM2 SNP309 in DLBCL (n=102). The presence of TP53 mutations (12.7%) correlated with a poor lymphoma-specific and progression-free survival, and a particularly pronounced effect was observed in the germinal center subtype. Neither the MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. In paper II, we applied pyrosequencing to measure the level of p16INK4a methylation in DLBCL (n=113). Thirty-seven percent of cases displayed p16INK4a methylation; however, no clear association could be observed between degree of methylation and clinical characteristics or lymphoma-specific survival.

    In papers III–IV, we investigated the prognostic role of MDM2 SNP309 (n=418) and TP53 mutation (n=268) in CLL. No correlation was observed between any particular MDM2 SNP309 genotype and time to treatment and overall survival. Furthermore, no association was found between the different MDM2 SNP309 genotypes and established CLL prognostic markers. TP53 mutations were detected in 3.7% of CLL patients; where the majority showed a concomitant 17p-deletion and only three carried TP53 mutations without 17p-deletion. We confirmed a significantly shorter overall survival and time to treatment in patients with both TP53 mutation and 17p-deletion.

    Altogether, our studies could confirm the negative prognostic impact of TP53 mutations in DLBCL, whereas MDM2 SNP309 and TP53 codon 72 polymorphisms appear to lack clinical relevance. We also question the role of p16INKa methylation as a poor-prognostic factor in DLBCL. Finally, the presence of TP53 mutation in CLL appears to be rare at disease onset and instead arise during disease progression.

  • 1089. Zambrano, Regina M.
    et al.
    Wohler, Elizabeth
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Thuresson, Ann-Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Cutting, Garry R.
    Batista, Denise A.
    Unbalanced translocation 9;16 in two children with dysmorphic features, and severe developmental delay: Evidence of cross-over within derivative chromosome 9 in patient #12011Inngår i: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 54, nr 2, s. 189-193Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe 2 children with dysmorphic features, and severe developmental delay presenting with overlapping unbalanced translocations of 9q34.3 and 16p13. Patient #1: A 4 year old African-American female with normal karyotype with a pericentric inversion on one chromosome 9 known to be a benign variant. Low resolution array CGH revealed a single BAC clone loss at 9q34.3 and a single BAC clone gain at 16p13.3, confirmed by FISH. Whole genome SNP array analysis refined these findings, identifying a terminal 1.28 Mb deletion (138,879,862-140,164,310) of 9q34.3 and a terminal 1.62 Mb duplication (45,320-1,621,753) of 16p13.3. Sub-telomeric FISH showed an unbalanced cryptic translocation involving the inverted chromosome 9 and chromosome 16. FISH of the father showed a balanced t(9;16) (q34.3;p13.3) involving the non-inverted chromosome 9, and a pericentric inversion on the normal 9 homologous chromosome. The presence of two rearrangements on chromosome 9, both an unbalanced translocation and a pericentric inversion, indicates recombination between the inverted and derivative 9 homologues from her father. Patient #2: A 1 year old Iraqi-Moroccan female with normal karyotype. Array-CGH identified a 0.56 Mb deletion of 9q34.3 (139,586,637-140,147,760) and an 11.31 Mb duplication of 16p13.3p13.13 (31,010-11,313,519). Maternal FISH showed a balanced t(9;16)(q34.3;p13.13). Both patients present with similar clinical phenotype.

  • 1090.
    Zander, Cecilia Soussi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Beckwith-Wiedemann Syndrome Revisited.2015Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 9Artikkel i tidsskrift (Fagfellevurdert)
  • 1091.
    Zander, Cecilia Soussi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Soussi, Thierry
    Breast-cancer stromal cells with TP53 mutations.2008Inngår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, nr 15Artikkel i tidsskrift (Fagfellevurdert)
  • 1092. Zeisel, Amit
    et al.
    Munoz-Manchado, Ana B.
    Codeluppi, Simone
    Lonnerberg, Peter
    La Manno, Gioele
    Jureus, Anna
    Marques, Sueli
    Munguba, Hermany
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Rolny, Charlotte
    Castelo-Branco, Goncalo
    Hjerling-Leffler, Jens
    Linnarsson, Sten
    Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq2015Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 347, nr 6226, s. 1138-1142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature. Here, we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in the mouse somatosensory cortex and hippocampal CA1 region. We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex. We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location. We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting a mechanism for the maintenance of adult cell type identity.

  • 1093.
    Zelano, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Mikulovic, Sanja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Patra, Kalicharan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Kühnemund, Malte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Larhammar, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Emilsson, Lina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Leao, Richardson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants2013Inngår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 239, s. 73-81Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.

  • 1094. Zeller, Bernward
    et al.
    Glosli, Heidi
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ha, Shau-Yin
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Hasle, Henrik
    Abrahamsson, Jonas
    Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 x 10(9)/l. The NOPHO experience 1984-20142017Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, nr 3, s. 448-456Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC > 200 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 10(9)/l and 57 (6%) had WBC >= 200 x 10(9)/l. Patients with WBC >= 200 x 10(9)/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 x 10(9)/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.

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    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England..
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    Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia..
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    Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland..
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    Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy..
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    Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England..
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