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  • 1051. von Salomé, Jenny
    et al.
    Boonstra, Philip S.
    Karimi, Masoud
    Silander, Gustav
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Stenmark-Askmalm, Marie
    Gebre-Medhin, Samuel
    Aravidis, Christos
    Nilbert, Mef
    Lindblom, Annika
    Lagerstedt-Robinson, Kristina
    Genetic anticipation in Swedish Lynch syndrome families2017Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 10, artikkel-id e1007012Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

  • 1052.
    Vujic, Mihailo
    et al.
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Göteborg, Sweden.
    Bergman, Annika
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Göteborg, Sweden.
    Romanus, Bertil
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Göteborg, Sweden.
    Wahlström, Jan
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Göteborg, Sweden.
    Martinsson, Tommy
    Department of Clinical Genetics, Sahlgrenska University Hospital/East, Göteborg, Sweden.
    Hereditary multiple and isolated sporadic exostoses in the same kindred: identification of the causative gene (EXT2) and detection of a new mutation, nt112delAT, that distinguishes the two phenotypes.2004Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 13, nr 1, s. 47-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hereditary multiple exostoses (HME) is a well known autosomal dominant hereditary orthopedic disorder. Isolated exostoses, on the other hand, occur as sporadic events or as secondary post-traumatic sequel. The occurrence of solitary exostoses in individuals from pedigrees affected with HME may distort conclusions about carrier status and/or diagnosis. Both conditions are potentially malignant and both are associated with genetic alterations in either EXT1 or EXT2 genes. In this study, we present a seven-generation family from western Sweden consisting of 170 blood relatives, 38 of whom had multiple cartilaginous exostoses, while 8 had isolated exostoses. Linkage analysis aimed to discern one of the known EXT genes demonstrated linkage of the HME phenotype to the EXT2 gene. Subsequent mutation analysis revealed a novel mutation, nt112delAT, in this gene. All carriers of the detected mutation had multiple exostoses, indicating full penetrance. None of the pedigree members with isolated exostoses were carriers of the detected mutation. Two of the mutation carriers developed chondrosarcoma yielding a 5.2% risk of malignant development for this mutation. The detection of this mutation has enabled us to provide appropriate genetic counseling concerning this complex situation.

  • 1053.
    Vymetalkova, Veronika
    et al.
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology & Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
    Vodicka, Pavel
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology & Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pague, Czech Republic.
    Pardini, Barbara
    Human Genetics Foundation, (HuGeF), Torino, Italy.
    Rosa, Fabio
    Human Genetics Foundation, (HuGeF), Torino, Italy.
    Levy, Miroslav
    Department of Surgery, 1st Faculty of Medicine, Thomayer Hospital, Charles University, Prague, Czech Republic.
    Schneiderova, Michaela
    Department of Surgery, General University Hospital, Prague, Czech Republic.
    Liska, Vaclav
    Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Czech Republic; Department of Surgery, Teaching Hospital & Medical School in Pilsen, Charles University, Pilsen, Czech Republic.
    Vodickova, Ludmila
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology & Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic.
    Nilsson, Torbjörn K.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Farkas, Sanja A.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature2016Inngår i: Epigenomics, ISSN 1750-1911, Vol. 8, nr 9, s. 1193-1207Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: The aim of the present study is to address a genome-wide search for novel methylation biomarkers in the rectal cancer (RC), as only scarce information on methylation profile is available.

    Materials and methods: We analyzed methylation status in 25 pairs of RC and adjacent healthy mucosa using the Illumina Human Methylation 450 BeadChip.

    Results: We found significantly aberrant methylation in 33 genes. After validation of our results by pyrosequencing, we found a good agreement with our findings. The BPIL3 and HBBP1 genes resulted hypomethylated in RC, whereas TIFPI2, ADHFE1, FLI1 and TLX1 were hypermethylated. An external validation by TCGA datasets confirmed the results.

    Conclusion: Our study, with external validation, has demonstrated the feasibility of using specific methylated DNA signatures for developing biomarkers in RC.

  • 1054.
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Integrating genome and epigenome in human disease2009Inngår i: Epigenomics / [ed] Anne Ferguson-Smith, John Greally & Robert Martiniensen, Dordrecht: Springer Science+Business Media B.V., 2009, s. 343-368Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    Transcription factors (TFs) and the core components of the epigenome, DNA methylation and histone modifications interact in the epigenetic machinery. Expression of key three-four selected transcription factors can dedifferentiate differentiated cells into induced pluripotent stem cells with a totally distinct epigenome. Out of the around 2,000 nuclear proteins, around 350 are known to cause disease when mutated. The conditions range from rare syndromes to common diseases. Mutations are found in all components of the epigenetic machinery, e.g. proteins mediating DNA methylation and those binding to methylated cytosine, histone proteins and enzymes adding or removing modifications to histone tails, those binding to the modifications as well as proteins in the basal transcription machinery. Sequence specific transcription factors are the most abundant nuclear proteins and mutations in them cause a wide range of diseases affecting different organs in the developing or mature organism. Even if a mutated protein is present in most or all cell-types, a specific disease is often found only in one or a few types. The reason for this is unclear and an interesting topic for future research. One hypothesis is that the disease is caused by the mutated protein interacting with other tissue restricted proteins. Technical breakthroughs like chromatin immunoprecipitation and analysis on next generation sequencers (ChIP-seq) mean that these processes can be systematically studied.

     

  • 1055.
    Waggott, Daryl
    et al.
    Stanford University.
    Mattsson, C. Mikael
    Gymnastik- och idrottshögskolan, GIH, Institutionen för idrotts- och hälsovetenskap.
    Wheeler, Matthew
    Stanford University.
    Ashley, Euan A.
    Stanford University.
    The Genomics of Extreme Athletes. The ELITE Study (Exercise at the Limit - Inherited Traits of Endurance).2016Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Health exists as a spectrum from disease to some outlier physiological optimum. To date most molecular genetic research has focused on disease states and less on extreme health populations. We hypothesize that interrogating outlier elite endurance athletes, with strict physiological eligibility criteria, will inform cardiovascular research through the identification of complementary pathways and therapeutic targets. Eligibility criteria for the ELITE study required a lifetime VO2max, which measures maximal oxygen consumption during peak aerobic exercise, at a threshold estimated to be attainable in less than 1 in 50,000 people (men  80ml/kg/min; women 65ml/kg/min). VO2max is reported to have substantial genetic influence (h2~0.5) and is correlated with endurance sport performance along with work efficiency. Several well documented cases of athletic outliers have been tied to rare genetic variants including the Finnish cross country skier Mäntyranta (EPOR) and  Priscilla Lopes-Schliep (LMNA). In the later, the same domain of the LMNA gene is related to rare forms of muscular dystrophy. Additionally, adaptive hypoxia variations have been identified in high altitude populations in Tibet (EPAS1), Andes and Ethiopia. To date we have sequenced 268 ELITE participants using clinically enhanced exomes and run 550 samples on high density multi-ethnic SNP chips. Preliminary analysis has focused on a combination of rare variant curation and common variation association. Rare variation curation included prioritization of LOF variants within candidate genes related to oxygen transport, muscle physiology and metabolism (i.e. PPARA, PPARGC1A, RYR2, ACTN3) and global gene screening using in silico weighted burden testing. Common variant association (the largest GWAS of its kind) has been used to support rare variant findings and identify non-coding and structural variant association signals. We believe that our methodology of combining rare LOF variants with common variation association in a population with extreme endurance physiology will systematically identify pleiotropic genes with both protective and pathogenic features similar to PCSK9.

  • 1056.
    Wahlberg, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Busche, Stephan
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Raine, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Sinnett, Daniel
    St Justine Univ Hlth Ctr, Res Ctr, Montreal, PQ, Canada.;Univ Montreal, Dept Pediat, Montreal, PQ, Canada..
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands2016Inngår i: Epigenomics, ISSN 1750-1911, Vol. 8, nr 10, s. 1367-1387Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

  • 1057. Wahlberg, Per
    et al.
    Lundmark, Anders
    Nordlund, Jessica
    Busche, Stephan
    Raine, Amanda
    Tandre, Karolina
    Rönnblom, Lars
    Sinnett, Daniel
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Pastinen, Tomi
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands2016Inngår i: Epigenomics, ISSN 1750-1911, Vol. 8, nr 10, s. 1367-1387Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

  • 1058.
    Wallerman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Genome-Wide Studies of Transcriptional Regulation in Mammalian Cells2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The key to the complexity of higher organisms lies not in the number of protein coding genes they carry, but rather in the intrinsic complexity of the gene regulatory networks. The major effectors of transcriptional regulation are proteins called transcription factors, and in this thesis four papers describing genome-wide studies of seven such factors are presented, together with studies on components of the chromatin and transcriptome.

    In Paper I, we optimized a large-scale in vivo method, ChIP-chip, to study protein – DNA interactions using microarrays. The metabolic-disease related transcription factors USF1, HNF4a and FOXA2 were studied in 1 % of the genome, and a surprising number of binding sites were found, mostly far from annotated genes.

    In Paper II, a novel sequencing based method, ChIP-seq, was applied to FOXA2, HNF4a and GABPa, allowing a true genome-wide view of binding sites. A large overlap between the datasets were seen, and molecular interactions were verified in vivo. Using a ChIP-seq specific motif discovery method, we identified both the expected motifs and several for co-localized transcription factors.

    In Paper III, we identified and studied a novel transcription factor, ZBED6, using the ChIP-seq method. Here, we went from one known binding site to several hundred sites throughout the mouse genome. Finally, in Paper IV, we studied the chromatin landscape by deep sequencing of nucleosomal DNA, and further used RNA-sequencing to quantify expression levels, and extended the knowledge about the binding profiles for the transcription factors NFY and TCF7L2.

  • 1059.
    Wallerman, Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Bysani, Madhu Sudhan Reddy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Motallebipour, Mehdi
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Nucleosome landscape in HepG2 cells in relation to NFY, HNF4a and FOXA2 binding sitesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Nucleosomes are the building blocks that compact the DNA in the nucleus, thereby regulating its accessibility. Here we report a genome-wide nucleosome positioning analysis on the HepG2 cell line, based on deep sequencing of mononucleosomal DNA. In concordance with other studies, we found nucleosomes to be well positioned at the TSS, with a nucleosome free region in the proximal promoter. Focusing on the importance of nucleosomal positioning at distal elements we found that TFBS sites often are flanked by well-positioning nucleosomes at a distance that indicate that the TF complexes replaces the nucleosome, and we also find that some transposable elements have distinct nucleosomal signatures. To build on previous regulatory data for HepG2 cells we also produced ChIP-seq reads for the transcription factors NF-Y and TCF7L2 and correlate this to the HepG2 transcriptome as defined by RNA-seq and Pol-II ChIP-seq. NF-Y was found primarily at promoters, contrary to what has been suggested from previous studies, and binds genes involved in cell cycle and chromatin organization.

  • 1060.
    Wallerman, Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nord, Helena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bysani, Madhusudhan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Borghini, Lisa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    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.
    lobChIP: from cells to sequencing ready ChIP libraries in a single day2015Inngår i: Epigenetics & Chromatin, ISSN 1756-8935, E-ISSN 1756-8935, Vol. 8, artikkel-id 25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: ChIP-seq is the method of choice for genome-wide studies of protein-DNA interactions. We describe a new method for ChIP-seq sample preparation, termed lobChIP, where the library reactions are performed on crosslinked ChIP fragments captured on beads. Results: The lobChIP method was found both to reduce time and cost and to simplify the processing of many samples in parallel. lobChIP has an early incorporation of barcoded sequencing adaptors that minimizes the risk of sample cross-contamination and can lead to reduced amount of adaptor dimers in the sequencing libraries, while allowing for direct decross-linking and amplification of the sample. Conclusions: With results for histone modifications and transcription factors, we show that lobChIP performs equal to or better than standard protocols and that it makes it possible to go from cells to sequencing ready libraries within a single day.

  • 1061.
    Walsh, Sarah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Analysis of Immunoglobulin Genes and Telomeres in B cell Lymphomas and Leukemias2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    B cell lymphomas and leukemias are heterogeneous tumors with different cellular origins. Analysis of immunoglobulin (Ig) genes enables insight into the B cell progenitor, as Ig somatic hypermutation correlates with antigen-related B cell transit through the germinal center (GC). Also, restricted Ig variable heavy chain (VH) gene repertoires in B cell malignancies could imply antigen selection during tumorigenesis. The length of telomeres has been shown to differ between GC B cells and pre/post-GC B cells, possibly representing an alternative angle to investigate B cell tumor origin.

    Mantle cell lymphoma (MCL), previously postulated to derive from a naïve, pre-GC B cell, was shown to have an Ig-mutated subset (18/110 MCLs, 16%), suggestive of divergent cellular origin and GC exposure. Another subset of MCL (16/110, 15%), characterized by VH3-21/Vλ3-19 gene usage, alludes to a role for antigen(s) in pathogenesis, also possible for hairy cell leukemia (HCL) in which the VH3-30 gene (6/32, 19%) was overused. HCL consisted mainly of Ig-mutated cases (27/32, 84%) with low level intraclonal heterogeneity, contrasting with the proposed post-GC origin, for both Ig-mutated and Ig-unmutated HCLs. For MCL and HCL, derivation from naïve or memory marginal zone B cells which may acquire mutations without GC transit are tempting speculations, but currently little is known about this alternative immunological pathway. Heavily mutated Ig genes without intraclonal heterogeneity were demonstrated in lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (13/14, 93%), confirming that the precursor cell was transformed after GC affinity maturation. Telomere length analysis within 304 B cell tumors revealed variable lengths; shortest in the Ig-unmutated subset of chronic lymphocytic leukemia, longest in the GC-like subtype of diffuse large B cell lymphoma, and homogeneous in MCL regardless of Ig mutation status. However, telomere length is complex with regard to GC-related origin.

    In summary, this thesis has provided grounds for speculation that antigens play a role in MCL and HCL pathogenesis, although the potential antigens involved are currently unknown. It has also enabled a more informed postulation about the cellular origin of B cell tumors, which will ultimately enhance understanding of the biological background of the diseases.

  • 1062.
    Walther, Charles
    et al.
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nilsson, Jenny
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Hofvander, Jakob
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Jonson, Tord
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Mandahl, Nils
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Ora, Ingrid
    Skane Univ Hosp, Dept Pediat Oncol, S-22185 Lund, Sweden..
    Gisselsson, David
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Mertens, Fredrik
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Genetic Heterogeneity in Rhabdomyosarcoma Revealed by SNP Array Analysis2016Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, nr 1, s. 3-15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS.

  • 1063. Wang, Chuan
    et al.
    Ahlford, Annika
    Järvinen, Tiina M
    Nordmark, Gunnel
    Eloranta, Maija-Leena
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A
    Truedsson, Lennart
    Eriksson, Catharina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Sjöwall, Christopher
    Julkunen, Heikki
    Criswell, Lindsey A
    Graham, Robert R
    Behrens, Timothy W
    Kere, Juha
    Rönnblom, Lars
    Syvänen, Ann-Christine
    Sandling, Johanna K
    Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations2013Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, nr 9, s. 994-999Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case-control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

  • 1064.
    Wang, Chuan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Kokkonen, Heidi
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Johansson, Martin
    Seddighzadeh, Maria
    Padyukov, Leonid
    Rantapaa-Dahlqvist, Solbritt
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Preferential Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis in 2 Swedish Case-Control Studies2011Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, nr 10, s. 2130-2132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective.

    Two interferon regulatory factor 5 (IRF5) gene variants were examined for association with rheumatoid arthritis (RA).

    Methods.

    A total of 2300 patients with RA and 1836 controls were recruited from 2 independent RA studies in Sweden. One insertion-deletion polymorphism (CGGGG indel) and one single-nucleotide polymorphism (rs10488631) in the IRF5 gene were genotyped and analyzed within RA subgroups stratified by rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA).

    Results.

    The CGGGG indel was preferentially associated with the RF-negative (OR 1.29, p = 7.9 × 10−5) and ACPA-negative (OR 1.27, p = 7.3 × 10−5) RA subgroups compared to the seropositive counterparts. rs10488631 was exclusively associated within the seronegative RA subgroups (RF-negative: OR 1.24, p = 0.016; ACPA-negative: OR 1.27, p = 4.1 × 10−3).

    Conclusion.

    Both the CGGGG indel and rs10488631 are relevant for RA susceptibility, especially for seronegative RA.

  • 1065.
    Wang, Sen
    et al.
    School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China.
    Zhao, Guanghui
    Xi'an Honghui Hospital, Health Science Center of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Shao, Wanzhen
    School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China.
    Liu, Huan
    School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China.
    Wang, Weizhuo
    Orthopedic Department, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Wu, Cuiyan
    Orthopedic Department, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
    Lammi, Mikko
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China; School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China.
    Guo, Xiong
    Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, Shaanxi, China; School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, China.
    The Importance of Se-Related Genes in the Chondrocyte of Kashin-Beck Disease Revealed by Whole Genomic Microarray and Network Analysis.2018Inngår i: Biological Trace Element Research, ISSN 0163-4984, E-ISSN 1559-0720Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kashin-Beck disease (KBD) is an endemic, chronic, and degenerative osteoarthropathy. Selenium (Se) deficiency plays important role in the pathogenesis of KBD. We aimed to screen Se-related gene from chondrocytes of patients with KBD. Whole-genome oligonucleotide microarrays were used to detect differentially expressed genes. qRT-PCR was used to confirm the microarray results. Comparative Toxicogenomics Database (CTD) was used to screen Se-related genes from differentially expressed genes. Gene Ontology (GO) classifications and network analysis of Se-related genes were constituted by STRING online system. Three hundred ninety-nine differentially expressed genes were obtained from microarray. Among them, 54 Se-related genes were identified by CTD. The qRT-PCR validation showed that four genes expressed similarly with the ones in the microarray transcriptional profiles. The Se-related genes were categorized into 6 cellular components, 8 molecular functions, 44 biological processes, 10 pathways, and 1 network by STRING. The Se-related gene insulin-like growth factor binding protein 2 (IGFBP2), insulin-like growth factor binding protein 3 (IGFBP3), interleukin 6 (IL6), BCL2, apoptosis regulator (BCL2), and BCL2-associated X, apoptosis regulator (BAX), which involved in many molecular functions, biological processes, and apoptosis pathway may play important roles in the pathogenesis of KBD.

  • 1066.
    Wang, Sheng
    et al.
    China Agr Univ, Coll Biol Sci, Beijing, Peoples R China;Natl Inst Biol Sci, Beijing, Peoples R China;Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA.
    Mandell, Jeffrey D.
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA.
    Kumar, Yogesh
    Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.
    Sun, Nawei
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA.
    Morris, Montana T.
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA.
    Arbelaez, Juan
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA.
    Nasello, Cara
    Rutgers State Univ, Dept Genet, Piscataway, NJ USA;Rutgers State Univ, Human Genet Inst New Jersey, Piscataway, NJ USA.
    Dong, Shan
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA.
    Duhn, Clif
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA.
    Zhao, Xin
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA;Shanghai Jiatong Univ, Sch Med, Xinhua Hosp, Dept Tradit Chinese Med, Shanghai, Peoples R China.
    Yang, Zhiyu
    Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.
    Padmanabhuni, Shanmukha S.
    Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.
    Yu, Dongmei
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Ctr Genom Med, Boston, MA USA;Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA USA.
    King, Robert A.
    Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA;Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA.
    Dietrich, Andrea
    Univ Groningen, Univ Med Ctr Groningen, Dept Child & Adolescent Psychiat, Groningen, Netherlands.
    Khalifa, Najah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    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.
    Huang, Alden Y.
    Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA;Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA.
    Neale, Benjamin M.
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Ctr Genom Med, Boston, MA USA;Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA USA.
    Coppola, Giovanni
    Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA;Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA.
    Mathews, Carol A.
    Univ Florida, Dept Psychiat, Genet Inst, Gainesville, FL 32611 USA.
    Scharf, Jeremiah M.
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Ctr Genom Med, Boston, MA USA;Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA USA.
    Fernandez, Thomas V.
    Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA;Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA.
    Buxbaum, Joseph D.
    Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.
    De Rubeis, Silvia
    Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.
    Grice, Dorothy E.
    Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.
    Xing, Jinchuan
    Rutgers State Univ, Dept Genet, Piscataway, NJ USA;Rutgers State Univ, Human Genet Inst New Jersey, Piscataway, NJ USA.
    Heiman, Gary A.
    Rutgers State Univ, Dept Genet, Piscataway, NJ USA;Rutgers State Univ, Human Genet Inst New Jersey, Piscataway, NJ USA.
    Tischfield, Jay A.
    Rutgers State Univ, Dept Genet, Piscataway, NJ USA;Rutgers State Univ, Human Genet Inst New Jersey, Piscataway, NJ USA.
    Paschou, Peristera
    Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.
    Willsey, A. Jeremy
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, UCSF Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA;Univ Calif San Francisco, QBI, San Francisco, CA 94143 USA.
    State, Matthew W.
    Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA 94143 USA;Univ Calif San Francisco, QBI, San Francisco, CA 94143 USA.
    De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis2018Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 24, nr 13, s. 3441-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

  • 1067.
    Wang, Shuang
    et al.
    Department of Orthodontics, Stomatological Hospital, Key Laboratory of Environment and Genes Related to Diseases, Department of Public Health, College of Medicine, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
    Guo, Xiong
    Department of Orthodontics, Stomatological Hospital, Key Laboratory of Environment and Genes Related to Diseases, Department of Public Health, College of Medicine, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
    Wu, Xiao-ming
    The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
    Lammi, Mikko J
    Department of Biosciences, University of Eastern Finland, Kuopio, Finland.
    Genome-wide gene expression analysis suggests an important role of suppressed immunity in pathogenesis of Kashin-Beck disease.2012Inngår i: PloS one, ISSN 1932-6203, Vol. 7, nr 1, s. e28439-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To investigate the differences between the gene expression profiles in peripheral blood mononuclear cells (PBMC) from normal controls and patients with Kashin-Beck disease (KBD).

    METHODS: Twenty KBD patients and 12 normal subjects were selected from a KBD-endemic area and divided into four pairs of KBD vs. control (KBD, n = 5 per pair; control, n = 3 per pair). RNAs were respectively isolated from KBD PBMCs and normal PBMCs. Gene expression profiles were analyzed by oligonucleotide microarray. The gene expression profiles in PBMCs from KBD patients and normal controls were compared and the differentially expressed genes were identified. The obtained microarray data was further confirmed by using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).

    RESULTS: Approximately 501 genes, corresponding to 2.4% of the total probe transcripts, showed a 2-fold change in differential expression. 19.4% (97 out of 501)of the differentially expressed genes were commonly detected in all the four pairs. Among the 97 differentially expressed genes, 83 genes were up-regulated and 14 genes were down-regulated, compared with those in the normal controls. Some differentially expressed genes were found to be related to functions such as immunity, metabolism, apoptosis, cystoskeleton and cell movement, and extracellular matrix. The validity of our microarray data were supported by the results of qRT-PCR assay.

    CONCLUSION: Differences in the PBMC gene expression profile between the KBD patients and the normal controls exhibited a similar pattern among all the four pairs of microarrays examined, indicating that the suppressed immunity may play an important role in the pathogenesis of KBD.

  • 1068. Wang, Tao
    et al.
    Moon, Jee-Young
    Wu, Yiqun
    Amos, Christopher I.
    Hung, Rayjean J.
    Tardon, Adonina
    Andrew, Angeline
    Chen, Chu
    Christiani, David C.
    Albanes, Demetrios
    van der Heijdendr, Erik H. F. M.
    Duell, Eric
    Rennert, Gadi
    Goodman, Gary
    Liu, Geoffrey
    Mckay, James D.
    Yuan, Jian-Min
    Field, John K.
    Manjer, Jonas
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Kiemeney, Lambertus A.
    Le Marchand, Loic
    Teare, M. Dawn
    Schabath, Matthew B.
    Johansson, Mattias
    Aldrich, Melinda C.
    Davies, Michael
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Tsao, Ming-Sound
    Caporaso, Neil
    Lazarus, Philip
    Lam, Stephen
    Bojesen, Stig E.
    Arnold, Susanne
    Wu, Xifeng
    Zong, Xuchen
    Hong, Yun-Chul
    Ho, Gloria Y. F.
    Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung Cancer Consortium2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 9, artikkel-id e0185660Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes.

  • 1069. Wang, Zheng
    et al.
    Iida, Aritoshi
    Miyake, Noriko
    Nishiguchi, Koji M.
    Fujita, Kosuke
    Nakazawa, Toru
    Alswaid, Abdulrahman
    Albalwi, Mohammed A.
    Kim, Ok-Hwa
    Cho, Tae-Joon
    Lim, Gye-Yeon
    Isidor, Bertrand
    David, Albert
    Rustad, Cecilie F.
    Merckoll, Else
    Westvik, Jostein
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Grigelioniene, Giedre
    Kou, Ikuyo
    Nakajima, Masahiro
    Ohashi, Hirohumi
    Smithson, Sarah
    Matsumoto, Naomichi
    Nishimura, Gen
    Ikegawa, Shiro
    Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 3, artikkel-id e0150555Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

  • 1070. Wanschers, Bas F. J.
    et al.
    Szklarczyk, Radek
    van den Brand, Mariel A. M.
    Jonckheere, An
    Suijskens, Janneke
    Smeets, Roel
    Rodenburg, Richard J.
    Stephan, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Helland, Ingrid B.
    Elkamil, Areej
    Rootwelt, Terje
    Ott, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    van den Heuvel, Lambert
    Nijtmans, Leo G.
    Huynen, Martijn A.
    A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability2014Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, nr 23, s. 6356-6365Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Complex III (cytochrome bc(1)) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c. Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83, hereafter named UQCC3, to be the ortholog of the fungal complex III assembly factor CBP4. We describe a homozygous c.59T > A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T > A mutation has a causal role in complex III deficiency.

  • 1071. Watt, Danielle L
    et al.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Burgers, Peter M
    Kunkel, Thomas A
    Replication of ribonucleotide-containing DNA templates by yeast replicative polymerases2011Inngår i: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 10, nr 8, s. 897-902Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The major replicative DNA polymerases of S. cerevisiae (Pols α, δ, and ɛ) incorporate substantial numbers of ribonucleotides into DNA during DNA synthesis. When these ribonucleotides are not removed in vivo, they reside in the template strand used for the next round of replication and could potentially reduce replication efficiency and fidelity. To examine if the presence of ribonucleotides in a DNA template impede DNA synthesis, we determined the efficiency with which Pols α, δ, and ɛ copy DNA templates containing a single ribonucleotide. All three polymerases can replicate past ribonucleotides. Relative to all-DNA templates, bypass of ribo-containing templates is slightly reduced, to extents that depend on the identity of the ribo and the sequence context in which it resides. Bypass efficiencies for Pols δ and ɛ were increased by increasing the dNTP concentrations to those induced by cellular stress, and in the case of Pol ɛ, by inactivating the 3'-exonuclease activity. Overall, ribonucleotide bypass efficiencies are comparable to, and usually exceed, those for the common oxidative stress-induced lesion 8-oxo-guanine.

  • 1072. Webb, Thomas R.
    et al.
    Erdmann, Jeanette
    Stirrups, Kathleen E.
    Stitziel, Nathan O.
    Masca, Nicholas G. D.
    Jansen, Henning
    Kanoni, Stavroula
    Nelson, Christopher P.
    Ferrario, Paola G.
    Koenig, Inke R.
    Eicher, John D.
    Johnson, Andrew D.
    Hamby, Stephen E.
    Betsholtz, Christer
    Ruusalepp, Arno
    Franzen, Oscar
    Schadt, Eric E.
    Bjoerkegren, Johan L. M.
    Weeke, Peter E.
    Auer, Paul L.
    Schick, Ursula M.
    Lu, Yingchang
    Zhang, He
    Dube, Marie-Pierre
    Goel, Anuj
    Farrall, Martin
    Peloso, Gina M.
    Won, Hong-Hee
    Do, Ron
    van Iperen, Erik
    Kruppa, Jochen
    Mahajan, Anubha
    Scott, Robert A.
    Willenborg, Christina
    Braund, Peter S.
    van Capelleveen, Julian C.
    Doney, Alex S. F.
    Donnelly, Louise A.
    Asselta, Rosanna
    Merlini, Pier A.
    Duga, Stefano
    Marziliano, Nicola
    Denny, Josh C.
    Shaffer, Christian
    El-Mokhtari, Nour Eddine
    Franke, Andre
    Heilmann, Stefanie
    Hengstenberg, Christian
    Hoffmann, Per
    Holmen, Oddgeir L.
    Hveem, Kristian
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Joeckel, Karl-Heinz
    Kessler, Thorsten
    Kriebel, Jennifer
    Laugwitz, Karl L.
    Marouli, Eirini
    Martinelli, Nicola
    McCarthy, Mark I.
    Van Zuydam, Natalie R.
    Meisinger, Christa
    Esko, Tonu
    Mihailov, Evelin
    Escher, Stefan A.
    Alver, Maris
    Moebus, Susanne
    Morris, Andrew D.
    Virtamo, Jarma
    Nikpay, Majid
    Olivieri, Oliviero
    Provost, Sylvie
    AlQarawi, Alaa
    Robertson, Neil R.
    Akinsansya, Karen O.
    Reilly, Dermot F.
    Vogt, Thomas F.
    Yin, Wu
    Asselbergs, Folkert W.
    Kooperberg, Charles
    Jackson, Rebecca D.
    Stahl, Eli
    Mueller-Nurasyid, Martina
    Strauch, Konstantin
    Varga, Tibor V.
    Waldenberger, Melanie
    Zeng, Lingyao
    Chowdhury, Rajiv
    Salomaa, Veikko
    Ford, Ian
    Jukema, J. Wouter
    Amouyel, Philippe
    Kontto, Jukka
    Nordestgaard, Borge G.
    Ferrieres, Jean
    Saleheen, Danish
    Sattar, Naveed
    Surendran, Praveen
    Wagner, Aline
    Young, Robin
    Howson, Joanna M. M.
    Butterworth, Adam S.
    Danesh, John
    Ardissino, Diego
    Bottinger, Erwin P.
    Erbel, Raimund
    Franks, Paul W.
    Girelli, Domenico
    Hall, Alistair S.
    Hovingh, G. Kees
    Kastrati, Adnan
    Lieb, Wolfgang
    Meitinger, Thomas
    Kraus, William E.
    Shah, Svati H.
    McPherson, Ruth
    Orho-Melander, Marju
    Melander, Olle
    Metspalu, Andres
    Palmer, Colin N. A.
    Peters, Annette
    Rader, Daniel J.
    Reilly, Muredach P.
    Loos, Ruth J. F.
    Reiner, Alex P.
    Roden, Dan M.
    Tardif, Jean-Claude
    Thompson, John R.
    Wareham, Nicholas J.
    Watkins, Hugh
    Willer, Cristen J.
    Samani, Nilesh J.
    Schunkert, Heribert
    Deloukas, Panos
    Kathiresan, Sekar
    Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease2017Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 69, nr 7, s. 823-836Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits. CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. (C) 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

  • 1073.
    Weibrecht, Irene
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Gavrilovic, Milan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Centrum för bildanalys.
    Lindbom, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Wählby, Carolina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Centrum för bildanalys.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Visualizing individual sequence-specific protein-DNA interactions in situManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Gene expression – a key feature for modulating cell fate – is regulated in part by histone modifications, which modulate accessibility of the chromatin to transcription factors. Until now, protein-DNA interactions have mostly been studied in bulk without retrieving spatial information from the sample or with poor sequence resolution. New tools are needed to reveal proteins interacting with specific DNA sequences in situ for further understanding of the orchestration of transcription control within the nucleus.

    We present herein an approach to visualize individual protein-DNA interactions within cells, based on the in situ proximity ligation assay (PLA). This assay, previously used for detection of protein-protein interactions in situ, was adapted for analysis of target protein-DNA interactions, using padlock probes to identify unique DNA sequences in complex genomes. As a proof-of-principle we detected histone H3 interacting with a 26 bp consensus sequence of the Alu-repeat abundantly expressed in the human genome, but absent in mice. However, the mouse genome contains a highly similar sequence, providing a model system to analyze the selectivity of the developed methods. Although efficiency of detection currently is limiting, we conclude that in situ PLA can be used to achieve a highly selective analysis of protein-DNA interactions in single cells.

  • 1074.
    Weibrecht, Irene
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Grundberg, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Simultaneous visualization of both signaling cascade activity and end-point gene expression in single cells2011Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 5, s. e20148-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have developed an approach for simultaneous detection of individual endogenous protein modifications and mRNA molecules in single cells in situ. For this purpose we combined two methods previously developed in our lab: in situ proximity ligation assay for the detection of individual protein interactions and -modifications and in situ detection of single mRNA molecules using padlock probes. As proof-of-principle, we demonstrated the utility of the method for simultaneous detection of phosphorylated PDGFRβ and DUSP6/MKP-3 mRNA molecules in individual human fibroblasts upon PDGF-BB stimulation. Further we applied drugs disrupting the PDGFRβ signaling pathway at various sites to show that this combined method can concurrently monitor the molecular effect of the drugs, i.e. inhibition of downstream signaling from the targeted node in the signaling pathway. Due to its ability to detect different types of molecules in single cells in situ the method presented here can contribute to a deeper understanding of cell-to-cell variations and can be applied to e.g. pinpoint effector sites of drugs in a signaling pathway.

  • 1075. Weisschuh, Nicole
    et al.
    Stingl, Katarina
    Audo, Isabelle
    Biskup, Saskia
    Bocquet, Beatrice
    Branham, Kari
    Burstedt, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    De Baere, Elfride
    De Vries, Meindert J.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Green, Andrew
    Heckenlively, John
    Leroy, Bart P.
    Meunier, Isabelle
    Traboulsi, Elias
    Wissinger, Bernd
    Kohl, Susanne
    Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia2018Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, nr 10, s. 1366-1371Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic alpha'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.

  • 1076.
    Wentzel, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Molecular and Clinical Characterization of Syndromes Associated With Intellectual Disability2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Intellectual disability (ID) affects approximately 1-3% of the population and is defined as having an IQ below 70 as well as a significant limitation in adaptive behavior.

    The implementation of chromosomal microarrays (CMA) into the field of clinical genetics has revolutionized the ability to find genetic aberrations responsible for different genetic disorders. Importantly. these technologies have allowed several new microdeletion and microduplication aberrations to be identified that otherwise would have escaped detection using more conventional methods. Finding the genetic etiology of a syndrome and its association to the phenotype is paramount to better health care, provision of tailored therapy, presymptomatic screening, accurate prognosis, recurrence risk evaluation and in some cases prenatal testing.

    Despite the plethora of new information available, there are still a number of clinical and genetic features we do not fully understand.

    The aim of this work was to identify regions and syndromes associated with ID by CMA analysis and to make a detailed clinical description of the affected patients’ phenotype.

    In paper I we studied the 22q11.2 duplication syndrome and presented two familial cases with a description of both their genotype and phenotype. Additionally, 36 cases harboring the duplication were reviewed to further delineate the phenotype of the syndrome.

    In paper II, we revealed two unrelated patients with a deletion at 6q14.1-q15 and a distinct phenotype. Together with one previously reported patient our study suggests that a novel, clinically recognizable microdeletion syndrome exists in these patients.

    In paper III the phenotype and genotype of six unrelated patients with partially overlapping microdeletions at 10p12.31-p11.21 were described. Taken together with a previously reported patient we propose that these findings represent a new contiguous gene syndrome.

    In paper IV, two sisters; one presenting with two tandem interstitial duplications and the other a large deletion over the same region (6q13-q16) were reported. The reason for the CNVs was a maternal de novo translocation. This is the first case describing the genotype and phenotype of this duplicated region at 6q13-q16.

    In conclusion, four different genetic aberrations involved in the etiology of ID and their corresponding phenotypes and candidate genes have been characterized.

  • 1077.
    Wentzel, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    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.
    A maternal de novo non-reciprocal translocation results in a 6q13-q16 deletion in one offspring and a 6q13-q16 duplication in another2014Inngår i: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 57, nr 6, s. 259-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions. (C) 2014 Elsevier Masson SAS. All rights reserved.

  • 1078.
    Wentzel, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    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.
    Unbalanced de novo translocation in mother resulting in one child with a 6q13-q16 deletion and one child with a 6q13-q16 duplicationManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Here we report on two sisters with reciprocal CNVs at 6q13-q16.1. Both the deletion and the duplication were inherited from the healthy mother carrying an insertion of 6q13-q16 to 15q11. The deleted region in one of the sisters has previously been described. However, to our knowledge this is the first report of a duplication at the region 6q13q16. In the report we submit a detailed phenotypical description of both patients as well as candidate genes for some of the various symptoms that the patients presented.

  • 1079. Wentzel, Christian
    et al.
    Rajcan-Separovic, Evica
    Ruivenkamp, Claudia A L
    Chantot-Bastaraud, Sandra
    Metay, Corinne
    Andrieux, Joris
    Annerén, Göran
    Gijsbers, Antoinet C J
    Druart, Luc
    Hyon, Capucine
    Portnoi, Marie-France
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Vincent-Delorme, Catherine
    Kant, Sarina G
    Steinraths, Michelle
    Marlin, Sandrine
    Giurgea, Irina
    Thuresson, Ann-Charlotte
    Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p112011Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, nr 9, s. 959-964Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

  • 1080.
    Wernersson, Sara
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Fc receptors and feedback enhancement of antibody responses2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Antibodies are important for the defence against microorganisms, but are also involved inpathological reactions such as allergy or autoimmunity. The exact mechanisms involved inregulation of antibody responses is still largely unknown. In this thesis, immune regulationby antibodies and the receptors they bind to (FcR), were investigated.

    IgG and IgE antibodies are known to enhance antibody responses to soluble antigens,such as bovine serum albumin (BSA), when given to mice as an immune complex. While IgE-mediated enhancement is mediated via the low affinity receptor for IgE, FcεRII (CD23), the receptors involved in IgG-mediated enhancement has not been clearly defined.To assess the role of FcRs for the enhancing effect by IgG, mice deficient of different FcRs were immunized with BSA alone or BSA/IgG complexes and actively produced BSA-specific IgG in serum was analyzed. We found that IgG-mediated enhancement was abrogated in mice deficient of the common γ-chain (lacking functional FcγRI, FcγRIII), wheras it was normal in mice selectively lacking FcγRIII. This suggests that expression of a functional FcγRI for the ability of IgG to enhance. Furthermore, the response to BSA/IsG in mice lacking the inhibitory FcγRIIB was several-fold higher, induced earlier, and was more long-lived than in wild type mice. These findings suggest that FcγRIIB prevents "over-production" of antibodies rather than inhibiting the initiation of a response.

    Immunization of mice with BSA and IgE triggered an early increase in the number ofIgG producing specific B cells, thus resembling a secondary response. Cell transferexperiments with CD23 deficient mice demonstrated that CD23 expression on B cells, butnot on follicular dendritic cells, was required and sufficient for the stimulatory ability ofIgE. These findings are compatible with the idea that IgE antibodies acts by increasing theability of B cells to take up antigens via CD23 and present them to T cells, which could bea stimulatory feedback mechanism involved in the perpetuation of allergic disease.

  • 1081.
    Wester, Kenneth
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Quantitative immunochemistry in tissue sections: With special reference to urinary bladder carcinoma1999Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Urinary bladder carcinoma affects about 2 000 people in Sweden every year. It is a heterogeneous disease and for adequate treatment decisions, prognostic tools are needed. Many of these are based on immunohistochemistry (MC) and hampered by poorly reproducible methodologies and subjective evaluations.This investigation aimed to evaluate and define the conditions for an objective and reproducible quantification of(MC) applied to routinely processed (formalin-fixed and paraffin-embedded) tissue material. To establish theseconditions, proliferation-related proteins, tumour-suppressor proteins and endothelial cell markers were studiedThree computerised colour-based image analysis methods, aiming to reduce user interaction, were developed and evaluated for variability and reproducibilty in quantification of IHC applied to histological sections. Themethods proved stable to variations in focus- and light-settings but revealed a sensitivity to poor IHC-qualityand choice of chromogen. Implementation of an external control system, used as base for computing theclassifier, further increased the stability.

    Using these methods, effects of varying tissue-handling and immunostaining conditions were analysed. Storageof both paraffin-blocks and -sections was deleterious to immunoreactivity but could be compensated for bytayloring of the heat induced epitope retrieval (HIER) protocol.A control system for MC based on cultured cells was developed to reflect variations in tissue-handling and IHC-conditions. Control and biopsy material showed similar sensitivity to section storage, MC- and HIER-protocolvariations. Furthermore, controls reflected variations in fixation time and proved stable to variations in sectionthickness.

  • 1082.
    Wester, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Bondeson, Marie-Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Edeby, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Clinical and molecular characterization of individuals with 18p deletion: a genotype-phenotype correlation2006Inngår i: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 140A, nr 11, s. 1164-1171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The deletion 18p syndrome is one of the most common chromosome abnormalities. The medical problems are mental and postnatal growth retardation, and sometimes malformations of the heart and brain. The individuals have some typical features, which might be easy to overlook and which are: ptosis, strabismus, hypertelorism, broad flat nose, micrognathia, big and low set ears. The aims of present study were to clinically and molecularly characterize the syndrome further in seven subjects with de novo 18p deletions and to perform genotype–phenotype correlation. All seven subjects had terminal deletions and no interstitial deletion was observed with subtelomeric FISH analyses. To define the extent of the 18p deletions and the parental origin of the deletion microsatellite- and FISH analyses were performed on genomic DNA and on lymphoblastoid cell lines of the study participants. Totally 19 chromosomes, 18 specific polymorphic microsatellite markers, and 5 BAC clones were used. The results revealed that the deletions were located in the centromeric region at 18p11.1 in four of the seven subjects. In the remaining three the breakpoints were located distal to 18p11.1 (18p11.21-p11.22). Four of the individuals had a paternal and three a maternal origin of the deletion. Genotype–phenotype correlation of the seven subjects suggests a correlation between the extent of the deleted region and the mental development. All the four children with a deletion in the centromeric region at 18p11.1 had a mental retardation (MR). Two of the three children with a more distal breakpoint (distal 18p11.21) had a normal mental development and one had a border-line mental retardation. There might be a critical region for the mental retardation located between 18p11.1 and 18p11.21. The children with a breakpoint at 18p11.1 had all a broad face, which was observed in only one of those with a more distal breakpoint, otherwise no genotype–phenotype correlation of the features was observed.

  • 1083.
    Westin, Gunnar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Molecular Genetics of Parathyroid Disease2009Inngår i: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 33, nr 11, s. 2224-2233Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Primary hyperparathyroidism (HPT) is often caused by a benign parathyroid tumor, adenoma; less commonly by multiglandular parathyroid disease/hyperplasia; and rarely by parathyroid carcinoma. Patients with multiple tumors require wider exploration to avoid recurrence and have increased risk for hereditary disease. Secondary HPT is a common complication of renal failure. Improved knowledge of the molecular background of parathyroid tumor development may help select patients for appropriate surgical treatment and can eventually provide new means of treatment. The present contribution summarizes more recent knowledge of parathyroid molecular genetics. METHODS: A literature search and review was made to evaluate the level of evidence concerning molecular biology and genetics of primary, secondary, and familial HPT according to criteria proposed by Sackett, with recommendation grading by Heinrich et al. RESULTS: Most parathyroid adenomas and hyperplastic glands are monoclonal lesions. Cyclin D1 gene (CCND1) translocation and oncogene action occur in 8% of adenomas; cyclin D1 overexpression is seen in 20% to 40% of parathyroid adenomas and in 31% of secondary hyperplastic glands. Somatic loss of one MEN1 allele is seen in 25% to 40% of sporadic parathyroid adenomas, half of which have inactivating mutation of the remaining allele. Inactivating somatic HRPT2 mutations are common in parathyroid carcinoma, often causing decreased expression of the protein parafibromin involved in cyclin D1 regulation. Aberrant regulation of Wnt/beta-catenin signaling may be important for parathyroid tumor development. CONCLUSIONS: Molecular genetic studies of parathyroid tumors are well designed basic experimental studies providing strong level III evidence, with data frequently confirmed by subsequent studies.

  • 1084. Westin, Maria
    et al.
    Rekabdar, Elham
    Blomstrand, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Käkkirurgi.
    Klintberg, Per
    Jontell, Mats
    Robledo-Sierra, Jairo
    Mutations in the genes for keratin-4 and keratin-13 in Swedish patients with white sponge nevus.2018Inngår i: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 47, nr 2, s. 152-157Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: White sponge nevus is a rare autosomal dominant disorder that affects the non-keratinised stratified squamous epithelium. Mutations in the genes that encode mucosa-specific keratin-4 and keratin-13 are strongly linked to the manifestation of white sponge nevus. This study involved mutational analysis of the genes encoding keratin-4 and keratin-13 in two Swedish families with white sponge nevus.

    METHODS: The diagnosis of white sponge nevus was based on disease history, clinical characteristics of the lesions and, in the majority of the cases, histopathological examination. Samples were collected from the affected buccal mucosa using buccal swabs. DNA was subsequently extracted and amplified using touchdown-PCR. The keratin-4 and keratin-13 genes were sequenced, and a genetic analysis was performed.

    RESULTS: A novel heterozygous missense mutation was identified in exon 1A of the keratin-4 gene in Family 2. In addition, previously reported heterozygous missense mutations were identified in the keratin-4 (E449K, A72V, Q156R, R208H) and keratin-13 (L115P) genes in both families.

    CONCLUSION: We describe a novel heterozygous missense mutation in the keratin-4 gene of a Swedish family with white sponge nevus. Our results support the notion that mutations in keratin-4 and keratin-13 are the underlying cause of white sponge nevus.

  • 1085. Westra, Harm-Jan
    et al.
    Martinez-Bonet, Marta
    Onengut-Gumuscu, Suna
    Lee, Annette
    Luol, Yang
    Teslovich, Nikola
    Worthington, Jane
    Martin, Javier
    Huizinga, Tom
    Klareskog, Lars
    Rantapää-Dahlqvist, Solbritt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Reumatologi.
    Chen, Wei-Min
    Quinlan, Aaron
    Todd, John A.
    Eyre, Steve
    Nigrovic, Peter A.
    Regersen, Peter K. G.
    Rich, Stephen S.
    Raychaudhuri, Soumya
    Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes2018Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, nr 10, s. 1366-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To define potentially causal variants for autoimmune disease, we fine-mapped(1,2) 76 rheumatoid arthritis (11,475 cases,15,870 controls)(3) and type 1 diabetes loci (9,334 cases, 11,111 controls)(4). After sequencing 799 1-kilobase regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We defined credible sets of <= 5 causal variants at 5 rheumatoid arthritis and 10 type 1 diabetes loci. We identified potentially causal missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28-CTLA4, and IL2RA. We also identified potential candidate causal variants at SIRPG and TNFAIP3. Using functional assays, we confirmed allele-specific protein binding and differential enhancer activity for three variants: the CD28-CTLA4 rs117701653 SNP, MEG3 rs34552516 indel, and TNFAIP3 rs35926684 indel.

  • 1086.
    Wetterbom, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Genome and Transcriptome Comparisons between Human and Chimpanzee2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The chimpanzee is humankind’s closest living relative and the two species diverged ~6 million years ago. Comparative studies of the human and chimpanzee genomes and transcriptomes are of great interest to understand the molecular mechanisms of speciation and the development of species-specific traits.

    The aim of this thesis is to characterize differences between the two species with regard to their genome sequences and the resulting transcript profiles. The first two papers focus on indel divergence and in particular, indels causing premature termination codons (PTCs) in 8% of the chimpanzee genes. The density of PTC genes is correlated with both the distance to the telomere and the indel divergence. Many PTC genes have several associated transcripts and since not all are affected by the PTC we propose that PTCs may affect the pattern of expressed isoforms. In the third paper, we investigate the transcriptome divergence in cerebellum, heart and liver, using high-density exon arrays. The results show that gene expression differs more between tissues than between species. Approximately 15% of the genes are differentially expressed between species, and half of the genes show different splicing patterns. We identify 28 cassette exons which are only included in one of the species, often in a tissue-specific manner. In the fourth paper, we use massive parallel sequencing to study the chimpanzee transcriptome in frontal cortex and liver. We estimate gene expression and search for novel transcribed regions (TRs). The majority of TRs are located close to genes and possibly extend the annotations. A subset of TRs are not found in the human genome. The brain transcriptome differs substantially from that of the liver and we identify a subset of genes enriched with TRs in frontal cortex.

    In conclusion, this thesis provides evidence of extensive genomic and transcriptomic variability between human and chimpanzee. The findings provide a basis for further studies of the underlying differences affecting phenotypic divergence between human and chimpanzee.

     

     

     

  • 1087.
    Wetterbom, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Bergström, Tomas
    Department of Animal breeding and genetics, SLU.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Global comparison of the human and chimpanzee transcriptomes using Affymetrix exon arraysManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We have used high-density exon arrays to study the human and chimpanzee transcriptome in cerebellum, heart and liver excluding probesets with mismatches to the chimpanzee. A total of 6281 RefSeq genes were expressed in our samples, the majority being expressed in two or more tissues, while ~ 6 % lacked expression in one of the species. A total of 923 RefSeq genes showed differences in expression between human and chimpanzes. More genes were differentially expressed in cerebellum (8.4 %) than in liver (6.9 %) and heart (4.5 %). Genes showing differential expression between species to a large extent also showed strong tissue-specific expression within species. Of the differentially expressed genes, more were upregulated in human versus chimpanzee, than the other way around. Liver had the highest proportion of genes with spliced genes (50 %), followed by cerebellum (40 %) and heart (30 %). Differentially expressed genes were often detected also as spliced (66-78 %). As one type of splice variation, we identified 26 genes with cassette exons, i.e. the exon is only included in one species. Cassette exon usage was tissue specific to a large extent and for the majority of cassette exons we observed expression in both human and chimpanzee in the other tissues. Taken together, our results indicate that splicing differences represents an extensive and important source of variation between species.

  • 1088.
    Wetterbom, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Genomik.
    Deep sequencing of the chimpanzee transcriptome identifies numerous novel transcribed regions in frontal cortex and liverManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We have performed the first global profiling of the chimpanzee transcriptome by using deep sequencing of cDNA from brain and liver. This enabled us to quantify expression of RefSeq transcripts, identify novel transcribed regions with no previous annotations in databases and additionally search for transcribed regions with no support in the human genome.

    Using stringent criteria for transcription, we identified 9,061 expressed RefSeq transcripts and 5,532 novel transcribed regions., of which the vast majority were found intronically in RefSeq transcripts and ~ 15 % mapped intergenically. In addition,  a little less than 150 novel transcribed regions in the chimpanzee appeared to be absent from the human reference sequence. Novel transcribed regions may represent new coding regions, untranslated regions unspliced mRNAs or diferent types of non-coding transcripts. The transcriptional profile of the brain stands out in several ways: a higher number of RefSeq transcripts were expressed in brain than in liver and novel transcribed regions were also more abundant in brain. Furthermore, we identified an interesting subset of RefSeq genes with a high density of novel transcribed regions scattered across the introns. These genes clustered in central pathways of the nervous system, with an overrepresentation of genes acting in the synapse and many of which have been associated to cognitive disorders in the human.

    Our results support the prevailing view of wide-spread transcription in mammalian genomes and further highlight the vast, mostly uncharacterized, transcript variability in the primate brain.

     

  • 1089. White, H.
    et al.
    Deprez, L.
    Corbisier, P.
    Hall, V.
    Lin, F.
    Mazoua, S.
    Trapmann, S.
    Aggerholm, A.
    Andrikovics, H.
    Akiki, S.
    Barbany, G.
    Boeckx, N.
    Bench, A.
    Catherwood, M.
    Cayuela, J-M
    Chudleigh, S.
    Clench, T.
    Colomer, D.
    Daraio, F.
    Dulucq, S.
    Farrugia, J.
    Fletcher, L.
    Foroni, L.
    Ganderton, R.
    Gerrard, G.
    Gineikiene, E.
    Hayette, S.
    El Housni, H.
    Izzo, B.
    Jansson, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Johnels, P.
    Jurcek, T.
    Kairisto, V.
    Kizilors, A.
    Kim, D-W
    Lange, T.
    Lion, T.
    Polakova, K. M.
    Martinelli, G.
    McCarron, S.
    Merle, P. A.
    Milner, B.
    Mitterbauer-Hohendanner, G.
    Nagar, M.
    Nickless, G.
    Nomdedeu, J.
    Nymoen, D. A.
    Leibundgut, E. O.
    Ozbek, U.
    Pajic, T.
    Pfeifer, H.
    Preudhomme, C.
    Raudsepp, K.
    Romeo, G.
    Sacha, T.
    Talmaci, R.
    Touloumenidou, T.
    Van der Velden, V. H. J.
    Waits, P.
    Wang, L.
    Wilkinson, E.
    Wilson, G.
    Wren, D.
    Zadro, R.
    Ziermann, J.
    Zoi, K.
    Mueller, M. C.
    Hochhaus, A.
    Schimmel, H.
    Cross, N. C. P.
    Emons, H.
    A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR2015Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, nr 2, s. 369-376Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08 +/- 0.13 x 10(6), 1.08 +/- 0.11 x 10(5), 1.03 +/- 0.10 x 10(4), 1.02 +/- 0.09 x 10(3), 1.04 +/- 0.10 x 10(2) and 10.0 +/- 1.5 copies/mu l. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/;CRM code ERM-AD623a-f).

  • 1090.
    Wibom, Carl
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ghasimi, Soma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Van Loo, Peter
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lau, Ching
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12, s. e47929-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

  • 1091.
    Wiklundh, E.
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Hellström, Cecilia
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Van Moorsel, C. H.
    St Antonius Hosp Pulmonol, Nieuwegein, Netherlands..
    Grutters, J. C.
    St Antonius Hosp, Dept Pulmonol, NL-3435 CM Nieuwegein, Netherlands..
    Nilsson, Peter
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap.
    Crestani, B.
    Hop Bichat Claude Bernard, Serv Pneumol, Paris, France..
    The Autoimmune Repertoire in Idiopathic Pulmonary Fibrosis2018Inngår i: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 197Artikkel i tidsskrift (Annet vitenskapelig)
  • 1092.
    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.

  • 1093.
    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)
  • 1094.
    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.

  • 1095.
    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.

  • 1096. 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.

  • 1097.
    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.

  • 1098.
    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.

  • 1099. 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.

  • 1100. 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.

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