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  • 1.
    de Vries, Paul S.
    et al.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Sabater-Lleal, Maria
    Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona, Spain;Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.
    Huffman, Jennifer E.
    NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;Framingham Heart Dis Epidemiol Study, Framingham, MA USA;Vet Affairs VA Boston Healthcare Syst, Ctr Populat Genom, Jamaica Plain, MA USA.
    Marten, Jonathan
    Univ Edinburgh, Western Gen Hosp, MRC, Human Genet Unit,Inst Genet & Mol Genet & Pathol, Edinburgh, Midlothian, Scotland.
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.
    Pankratz, Nathan
    Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.
    Bartz, Traci M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
    de Haan, Hugoline G.
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands.
    Delgado, Graciela E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.
    Eicher, John D.
    NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.
    Martinez-Perez, Angel
    Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona, Spain.
    Ward-Caviness, Cavin K.
    US EPA, Natl Hlth & Environm Effects Res Lab, Chapel Hill, NC USA.
    Brody, Jennifer A.
    Univ Washington, Dept Med, Seattle, WA USA.
    Chen, Ming-Huei
    NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.
    de Maat, Moniek P. M.
    Erasmus MC, Dept Hematol, Rotterdam, Netherlands.
    Franberg, Mattias
    Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.
    Gill, Dipender
    Imperial Coll London, Dept Epidemiol & Biostat, London, England;Imperial Coll London, Dept Stroke Med, London, England.
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany;Friedrich Schiller Univ Jena, Inst Nutr, Mannheim, Germany.
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Manuel Soria, Jose
    Inst Invest Biomed St Pau, Unit Genom Complex Dis, Barcelona, Spain.
    Tang, Weihong
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA.
    Tofler, Geoffrey H.
    Univ Sydney, Royal North Shore Hosp, Sydney, NSW, Australia.
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Vlieg, Astrid van Hylckama
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands.
    Seshadri, Sudha
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA;Boston Univ, Dept Neurol, Boston, MA 02215 USA;Univ Texas Hlth Sci Ctr San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX 78229 USA.
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA;Baylor Univ, Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Davies, Neil M.
    Univ Bristol, Bristol Med Sch, MRC, Integrat Epidemiol Unit, Bristol, Avon, England.
    Giese, Anne-Katrin
    Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA.
    Ikram, M. Kamran
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Neurol, Rotterdam, Netherlands.
    Kittner, Steven J.
    Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA;Baltimore VA Med Ctr, Baltimore, MD USA.
    McKnight, Barbara
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
    Psaty, Bruce M.
    Univ Washington, Dept Med, Seattle, WA USA;Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA;Kaiser Permanente Washington, Kaiser Permanente Washington Res Inst, Seattle, WA USA.
    Reiner, Alex P.
    Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA;Kaiser Permanente Washington, Kaiser Permanente Washington Res Inst, Seattle, WA USA;Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Sargurupremraj, Muralidharan
    Univ Bordeaux, INSERM, U1219, Bordeaux Populat Hlth Res Ctr, Bordeaux, France.
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA;Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA.
    Hamsten, Anders
    Karolinska Inst, Dept Med, Cardiovasc Med Unit, Stockholm, Sweden;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany;Synlab Holding Deutschland GmbH, Synlab Acad, Mannheim, Germany;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.
    Rosendaal, Frits R.
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands;Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Thrombosis & Hemostasis, Leiden, Netherlands.
    Carlos Souto, Juan
    Hosp Santa Creu & Sant Pau, Unitat Hemostasia & Trombosi, Barcelona, Spain.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Imperial Coll London, Dept Epidemiol & Biostat, London, England;Imperial Coll London, Sch Publ Hlth, Publ Hlth England Ctr Environm & Hlth, MRC, London, England;Imperial Coll London, UK Dementia Res Inst, London, England.
    Johnson, Andrew D.
    NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;Framingham Heart Dis Epidemiol Study, Framingham, MA USA.
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA.
    O'Donnell, Christopher J.
    NHLBI, Populat Sci Branch, NIH, Framingham, MA USA;VA Boston Healthcare Syst, Cardiol Sect, West Roxbury, MA USA.
    Smith, Nicholas L.
    Univ Washington, Dept Epidemiol, 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA;Kaiser Permanente Washington, Kaiser Permanente Washington Res Inst, Seattle, WA USA;US Dept Vet Affairs, Seattle Epidemiol Res & Informat Ctr, Off Res & Dev, Seattle, WA USA.
    A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology2019In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 133, no 9, p. 967-977Article in journal (Refereed)
    Abstract [en]

    Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

  • 2.
    Huan, Tianxiao
    et al.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, , Bethesda, MD USA.
    Peng, Fen
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Brown Fdn, McGovern Med Sch, Houston, TX USA.
    Guo, Yichen
    Harvard Univ, Dept Environm Hlth, Harvard TH Chan Sch Publ Hlth, Boston, MA USA; Harvard Univ, Dept Biostat, Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Mendelson, Michael
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA; Harvard Univ, Dept Cardiol, Boston Childrens Hosp, Boston, MA USA.
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Liu, Chunyu
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Ma, Jiantao
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Richard, Melissa
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Brown Fdn, McGovern Med Sch, Houston, TX USA.
    Agha, Golareh
    Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA.
    Guan, Weihua
    Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN USA.
    Almli, Lynn M.
    Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA.
    Conneely, Karen N.
    Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA.
    Keefe, Joshua
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Hwang, Shih-Jen
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Johnson, Andrew D.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Brown Fdn, McGovern Med Sch, Houston, TX USA.
    Liang, Liming
    Harvard Univ, Dept Biostat, Harvard TH Chan Sch Publ Hlth, Boston, MA USA; Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    Leyy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD USA.
    Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4267Article in journal (Refereed)
    Abstract [en]

    Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

  • 3.
    Ma, Jiantao
    et al.
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Tufts Univ, Nutr Data Sci, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Nano, Jana
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany;German Ctr Diabet Res, Munich, Germany.
    Ding, Jingzhong
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Zheng, Yinan
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Hennein, Rachel
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Liu, Chunyu
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Dept Biostat, Boston, MA 02215 USA.
    Speliotes, Elizabeth K.
    Univ Michigan, Sch Med, Ann Arbor, MI USA.
    Huan, Tianxiao
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Mendelson, Michael M.
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Harvard Med Sch, Dept Cardiol, Boston Childrens Hosp, Boston, MA 02115 USA.
    Joehanes, Roby
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Long, Michelle T.
    Boston Univ, Sch Med, Dept Med, Gastroenterol Sect, Boston, MA 02118 USA.
    Liang, Liming
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Smith, Jennifer A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Reynolds, Lindsay M.
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Ghanbari, Mohsen
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Mashhad Univ Med Sci, Sch Med, Dept Genet, Mashhad, Razavi Khorasan, Iran.
    Muka, Taulant
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    van Meurs, Joyce B. J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Alferink, Louise J. M.
    Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands.
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Imperial Coll London, Dept Biostat & Epidemiol, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London, England.
    Ratliff, Scott
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Zhao, Wei
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Bielak, Lawrence
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Kardia, Sharon L. R.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Peyser, Patricia A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Ning, Hongyan
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    VanWagner, Lisa B.
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA;Northwestern Univ, Dept Med, Feinberg Sch Med, Div Gastroenterol & Hepatol, Chicago, IL 60611 USA.
    Lloyd-Jones, Donald M.
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Carr, John Jeffrey
    Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA.
    Greenland, Philip
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Lichtenstein, Alice H.
    Tufts Univ, USDA, Human Nutr Res Ctr Aging, Cardiovasc Nutr Lab, Boston, MA 02111 USA.
    Hu, Frank B.
    Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.
    Liu, Yongmei
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Hou, Lifang
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Murad, Sarwa Darwish
    Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands.
    Levy, Daniel
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease2019In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 5, p. 1073-1083Article in journal (Refereed)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 x 10(-6)) with replication at Bonferroni-corrected P < 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10(-4)). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

  • 4.
    Malhotra, Rajeev
    et al.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Mauer, Andreas C.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Cardenas, Christian L. Lino
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA.
    Yao, Jie
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA.
    Zhang, Xiaoling
    Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA;Boston Univ, Sch Med, Dept Med, Biomed Genet Sect, Boston, MA 02118 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Wunderer, Florian
    Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA;Univ Hosp Frankfurt, Dept Anesthesiol Intens Care Med & Pain Therapy, Frankfurt, Germany.
    Smith, Albert, V
    Iceland Heart Assoc, Kopavogur, Iceland;Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.
    Wong, Quenna
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
    Pechlivanis, Sonali
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
    Hwang, Shih-Jen
    Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA.
    Wang, Judy
    Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA.
    Lu, Lingyi
    Wake Forest Sch Med, Winston Salem, NC 27101 USA.
    Nicholson, Christopher J.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Shelton, Georgia
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Buswell, Mary D.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Barnes, Hanna J.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Sigurslid, Haakon H.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Slocum, Charles
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    O'Rourke, Caitlin
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA.
    Rhee, David K.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Bagchi, Aranya
    Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.
    Nigwekar, Sagar U.
    Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA.
    Buys, Emmanuel S.
    Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.
    Campbell, Catherine Y.
    Midatlant Permanente Med Grp, Rockville, MD USA.
    Harris, Tamara
    NIA, Bethesda, MD 20892 USA.
    Budoff, Matthew
    Harbor UCLA Med Ctr, Dept Med, Div Cardiol, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.
    Criqui, Michael H.
    Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA.
    Rotter, Jerome, I
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA.
    Johnson, Andrew D.
    Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA.
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA.
    Franceschini, Nora
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA.
    Debette, Stephanie
    Univ Bordeaux, INSERM, U1219, Bordeaux, France;Univ Hosp Bordeaux, Dept Neurol, Bordeaux, France.
    Hoffmann, Udo
    Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA.
    Kaelsch, Hagen
    Alfried Krupp Hosp, Dept Cardiol, Essen, Germany;Witten Herdecke Univ, Witten, Germany.
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany;Univ Bonn, Dept Genom, Life & Brain GmbH, Bonn, Germany.
    Sigurdsson, Sigurdur
    Iceland Heart Assoc, Kopavogur, Iceland.
    Freedman, Barry, I
    Wake Forest Sch Med, Winston Salem, NC 27101 USA.
    Bowden, Donald W.
    Wake Forest Sch Med, Winston Salem, NC 27101 USA.
    Jckel, Karl-Heinz
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
    Moebus, Susanne
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany;Univ Hosp Essen, Ctr Urban Epidemiol, Essen, Germany.
    Erbel, Raimund
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
    Feitosa, Mary F.
    Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA.
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykjavik, Iceland.
    Thanassoulis, George
    Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA;McGill Univ, Dept Med, Hlth Ctr, Montreal, PQ, Canada.
    Zapol, Warren M.
    Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA.
    Lindsay, Mark E.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Bloch, Donald B.
    Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA;Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.
    Post, Wendy S.
    Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA.
    O'Donnell, Christopher J.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02115 USA;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA;US Dept Vet Affairs, Boston, MA 02203 USA.
    HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 11, p. 1580-+Article in journal (Refereed)
    Abstract [en]

    Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

  • 5.
    Yao, Chen
    et al.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Chen, George
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA; NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Keefe, Joshua
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Mendelson, Michael
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA;Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA.
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Sun, Benjamin B.
    Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England.
    Laser, Annika
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany.
    Maranville, Joseph C.
    Merck & Co Inc, MRL, Kenilworth, NJ 07033 USA.
    Wu, Hongsheng
    Wentworth Inst Technol, Comp Sci & Networking, Boston, MA 02115 USA.
    Ho, Jennifer E.
    Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Courchesne, Paul
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Lyass, Asya
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Dept Math & Stat, Boston, MA 02115 USA.
    Larson, Martin G.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
    Gieger, Christian
    German Ctr Diabet Res DZD, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany.
    Graumann, Johannes
    WG Kerckhoff Inst, Max Planck Inst Heart & Lung Res, Sci Serv Grp Biomol Mass Spectrometry, Ludwigstr 43, D-61231 Bad Nauheim, Germany.
    Johnson, Andrew D.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Danesh, John
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Dept Math & Stat, Boston, MA 02115 USA.
    Runz, Heiko
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.
    Hwang, Shih-Jen
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany.
    Liu, Chunyu
    Butterworth, Adam S.
    Wellcome Trust Sanger Inst, Dept Human Genet, Wellcome Trust Genome Campus, Cambridge CB10 1RQ, England;Univ Cambridge, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Cambridge CB1 8RN, England;Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gom, Cambridge CB1 8RN, England;Addenbrookes Hosp, British Heart Fdn, Cambridge Ctr Excellence, Div Cardiovasc Med, Cambridge CB2 0QQ, England.
    Suhre, Karsten
    Weill Cornell Med Qatar, Dept Physiol & Biophys, PO 24144, Doha, Qatar;Merck & Co Inc, MRL, Kenilworth, NJ 07033 USA.
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA.
    Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 3268Article in journal (Refereed)
    Abstract [en]

    Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

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