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      Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

      research-article
      1 , 2 , , 3 , 4 , 5 , 5 , 6 , 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 5 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 14 , 25 , 21 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 35 , 42 , 43 , 44 , 45 , 46 , 16 , 26 , 47 , 48 , 43 , 49 , 50 , 20 , 51 , 52 , 53 , 54 , 55 , 40 , 56 , 57 , 58 , 59 , 60 , 49 , 61 , 40 , 62 , 63 , 64 , 65 , 66 , 67 , 18 , 68 , 14 , 69 , 70 , 24 , 41 , 17 , 58 , 71 , 72 , 73 , 14 , 18 , 74 , 75 , 64 , 76 , 77 , 18 , 78 , 7 , 5 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 18 , 89 , 90 , 91 , 35 , 92 , 56 , 31 , 74 , 60 , 93 , 84 , 43 , 50 , 80 , 53 , 94 , 95 , 66 , Lifelines Cohort Study, 27 , 96 , 39 , 97 , 98 , 99 , 39 , 100 , 101 , 102 , 103 , 104 , 105 , 35 , 106 , 107 , 108 , 109 , 1 , 110 , 111 , 112 , 113 , 44 , 42 , 52 , 114 , 21 , 115 , 116 , 117 , 26 , 47 , 62 , 118 , 119 , 97 , 120 , 121 , 7 , 122 , 123 , 50 , 124 , 22 , 21 , 64 , 40 , 10 , 24 , 47 , 125 , 124 , 126 , 127 , 128 , 17 , 129 , 130 , 131 , 132 , 63 , 4 , 18 , 51 , 52 , 133 , 134 , 135 , 17 , 48 , 136 , 137 , 21 , 138 , 67 , 49 , 112 , 53 , 47 , 139 , 44 , 140 , 39 , 141 , 142 , 41 , 143 , 58 , 70 , 51 , 144 , 61 , 84 , 56 , 83 , 145 , 54 , 55 , 42 , 146 , 100 , 106 , 107 , 65 , 63 , 147 , 148 , 149 , 150 , 151 , 91 , 50 , 64 , 48 , 65 , 66 , 38 , 62 , 133 , 152 , 153 , 36 , 154 , 34 , 29 , 81 , 155 , 16 , 31 , 7 , 8 , 35 , 92 , 156 , 35 , 156 , 157 , 21 , 28 , 72 , 158 , 20 , 24 , 18 , 17 , 159 , 160 , 124 , 161 , 162 , 11 , 163 , 23 , 28 , 164 , 3 , 14 , 5 , , 165 , 166 ,
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          Abstract

          Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

          Abstract

          GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

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          Most cited references33

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          Is Open Access

          Genetic effects on gene expression across human tissues

          (2017)
          Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
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            Is Open Access

            The NHGRI GWAS Catalog, a curated resource of SNP-trait associations

            The National Human Genome Research Institute (NHGRI) Catalog of Published Genome-Wide Association Studies (GWAS) Catalog provides a publicly available manually curated collection of published GWAS assaying at least 100 000 single-nucleotide polymorphisms (SNPs) and all SNP-trait associations with P <1 × 10−5. The Catalog includes 1751 curated publications of 11 912 SNPs. In addition to the SNP-trait association data, the Catalog also publishes a quarterly diagram of all SNP-trait associations mapped to the SNPs’ chromosomal locations. The Catalog can be accessed via a tabular web interface, via a dynamic visualization on the human karyotype, as a downloadable tab-delimited file and as an OWL knowledge base. This article presents a number of recent improvements to the Catalog, including novel ways for users to interact with the Catalog and changes to the curation infrastructure.
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              Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease.

              Background Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown. Methods Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet. Results The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category. Conclusions Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).
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                Author and article information

                Contributors
                tuomas.kilpelainen@sund.ku.dk
                rao@wustl.edu
                ruth.loos@mssm.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                22 January 2019
                22 January 2019
                2019
                : 10
                : 376
                Affiliations
                [1 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, 2200 Denmark
                [2 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Environmental Medicine and Public Health, , The Icahn School of Medicine at Mount Sinai, ; New York, 10029 NY USA
                [3 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Center for Research on Genomics and Global Health, National Human Genome Research Institute, , National Institutes of Health, ; Bethesda, 20892 MD USA
                [4 ]ISNI 0000000089452978, GRID grid.10419.3d, Internal Medicine, Gerontology and Geriatrics, , Leiden University Medical Center, ; Leiden, 2300 RC The Netherlands
                [5 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Biostatistics, , Washington University School of Medicine, ; St. Louis, 63110 MO USA
                [6 ]ISNI 0000 0001 2190 5763, GRID grid.7727.5, Department of Genetic Epidemiology, , University of Regensburg, ; Regensburg, 93051 Germany
                [7 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Preventive Medicine, , Brigham and Women’s Hospital, ; Boston, 02215 MA USA
                [8 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; Boston, 02131 MA USA
                [9 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Clinical and Translational Epidemiology Unit, , Massachusetts General Hospital, ; Boston, 02114 MA USA
                [10 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Medicine, , Harvard Medical School, ; Boston, 02115 MA USA
                [11 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Clinical Pharmacology, William Harvey Research Instititute, , Barts and The London School of Medicine and Dentistry, Queen Mary University of London, ; London, EC1M 6BQ UK
                [12 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, , Harvard School of Public Health, ; Boston, 02115 MA USA
                [13 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Centre de Bioinformatique, , Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, ; Paris, 75015 France
                [14 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, , The University of Texas Health Science Center at Houston, ; Houston, 77030 TX USA
                [15 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Cardiovascular Division, Department of Medicine, , Washington University, ; St. Louis, 63110 MO USA
                [16 ]ISNI 0000000122483208, GRID grid.10698.36, Epidemiology, University of North Carolina Gillings School of Global Public Health, ; Chapel Hill, 27514 NC USA
                [17 ]The Institute for Translational Genomics and Population Sciences, Division of Genomic Outcomes, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, 90502 CA USA
                [18 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Epidemiology, , Erasmus University Medical Center, ; Rotterdam, 3015 CE The Netherlands
                [19 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Epidemiology, , University of Alabama at Birmingham, ; Birmingham, 35294 AL USA
                [20 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Statistical Genomics, Department of Genetics, , Washington University School of Medicine, ; St. Louis, 63108 MO USA
                [21 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Epidemiology, School of Public Health, , University of Michigan, ; Ann Arbor, 48109 MI USA
                [22 ]ISNI 0000 0004 1937 0407, GRID grid.410721.1, Jackson Heart Study, Department of Medicine, , University of Mississippi Medical Center, ; Jackson, 39213 MS USA
                [23 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Institute of Molecular Medicine, McGovern Medical School, , University of Texas Health Science Center at Houston, ; Houston, 77030 TX USA
                [24 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Sleep and Circadian Disorders, , Brigham and Women’s Hospital, ; Boston, 02115 MA USA
                [25 ]ISNI 0000000122986657, GRID grid.34477.33, Cardiovascular Health Research Unit, Biostatistics and Medicine, , University of Washington, ; Seattle, 98101 WA USA
                [26 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, , University of Edinburgh, ; Edinburgh, EH4 2XU UK
                [27 ]ISNI 0000 0004 0637 0221, GRID grid.185448.4, Genome Institute of Singapore, , Agency for Science Technology and Research, ; Singapore, 138672 Singapore
                [28 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Biostatistics, Boston University School of Public Health, ; Boston, 02118 MA USA
                [29 ]ISNI 0000 0001 2134 6519, GRID grid.411221.5, Postgraduate Program in Epidemiology, , Federal University of Pelotas, ; Pelotas, 96020220 RS Brazil
                [30 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Medical Research Council Integrative Epidemiology Unit, , University of Bristol, ; Bristol, BS8 2BN UK
                [31 ]ISNI 0000 0004 1937 0722, GRID grid.11899.38, Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), , University of São Paulo Medical School, ; São Paulo, 01246903 SP Brazil
                [32 ]Epidemiology and Biostatistics, University of Giorgia at Athens College of Public Health, Athens, 30602 GA USA
                [33 ]ISNI 0000 0004 0459 1231, GRID grid.412860.9, Public Health Sciences, Biostatistical Sciences, , Wake Forest University Health Sciences, ; Winston-Salem, 27157 NC USA
                [34 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Institute of Genetics and Molecular Medicine, , University of Edinburgh, ; Edinburgh, EH4 2XU UK
                [35 ]ISNI 0000 0004 0451 6143, GRID grid.410759.e, Saw Swee Hock School of Public Health, , National University Health System and National University of Singapore, ; Singapore, 117549 Singapore
                [36 ]ISNI 0000 0000 9458 5898, GRID grid.420802.c, Icelandic Heart Association, ; 201, Kopavogur, Iceland
                [37 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Biostatistics, , University of Michigan, ; Ann Arbor, 48109 MI USA
                [38 ]ISNI 0000 0000 9372 4913, GRID grid.419475.a, Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, , National Institute on Aging, National Institutes of Health, ; Baltimore, 21224 MD USA
                [39 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Estonian Genome Center, , University of Tartu, ; Tartu, 51010 Estonia
                [40 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Epidemiology, University of Groningen, , University Medical Center Groningen, ; Groningen, 9700 RB The Netherlands
                [41 ]CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, 59000 France
                [42 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, , Karolinska Institutet, Stockholm, ; Stockholm, 17177 Sweden
                [43 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Department of Biostatistical Sciences, , Wake Forest School of Medicine, ; Winston-Salem, 27157 NC USA
                [44 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Epidemiology and Biostatistics, , Imperial College London, ; London, W2 1PG UK
                [45 ]ISNI 0000 0001 2108 7481, GRID grid.9594.1, Department of Hygiene and Epidemiology, , University of Ioannina Medical School, ; Ioannina, 45110 Greece
                [46 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Molecular Genetics and Genomics Program, , Wake Forest School of Medicine, ; Winston-Salem, 27157 NC USA
                [47 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Cognitive Ageing and Cognitive Epidemiology, , The University of Edinburgh, ; Edinburgh, EH8 9JZ UK
                [48 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430014 China
                [49 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Biostatistics and Center for Statistical Genetics, , University of Michigan, ; Ann Arbor, 48109 MI USA
                [50 ]ISNI 0000000121885934, GRID grid.5335.0, MRC Epidemiology Unit, , University of Cambridge, ; Cambridge, CB2 0QQ UK
                [51 ]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Research Unit of Molecular Epidemiology, , Helmholtz Zentrum München, German Research Center for Environmental Health, ; Neuherberg, 85764 Germany
                [52 ]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Institute of Epidemiology, Helmholtz Zentrum München, , German Research Center for Environmental Health, ; Neuherberg, 85764 Germany
                [53 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, , Karolinska Institutet, ; Stockholm, 17177 Sweden
                [54 ]Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33014 Finland
                [55 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Clinical Chemistry, Finnish Cardiovascular Research Center—Tampere, Faculty of Medicine and Life Sciences, , University of Tampere, ; Tampere, 33014 Finland
                [56 ]GRID grid.419013.e, Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, ; Kuopio, 70100 Finland
                [57 ]College of Medicine, Biological Sciences and Psychology, Health Sciences, The Infant Mortality and Morbidity Studies (TIMMS), Leicester, LE1 7RH UK
                [58 ]ISNI 0000 0004 1760 7415, GRID grid.418712.9, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, ; Trieste, 34137 Italy
                [59 ]ISNI 0000 0001 2165 4204, GRID grid.9851.5, Department of Computational Biology, , University of Lausanne, ; Lausanne, 1015 Switzerland
                [60 ]ISNI 0000 0001 2223 3006, GRID grid.419765.8, Swiss Institute of Bioinformatics, ; 1015, Lausanne, Switzerland
                [61 ]ISNI 0000 0004 0489 0290, GRID grid.45203.30, Department of Gene Diagnostics and Therapeutics, Research Institute, , National Center for Global Health and Medicine, ; Tokyo, 1628655 Japan
                [62 ]ISNI 0000 0004 0623 9987, GRID grid.411843.b, Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, , Skåne University Hospital, ; Malmö, 20502 Sweden
                [63 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, University of Groningen, University Medical Center Groningen, Department of Cardiology, ; Groningen, 9700 RB The Netherlands
                [64 ]ISNI 0000000086837370, GRID grid.214458.e, Survey Research Center, Institute for Social Research, , University of Michigan, ; Ann Arbor, 48104 MI USA
                [65 ]ISNI 0000 0001 2264 7217, GRID grid.152326.1, Division of Epidemiology, Department of Medicine, , Vanderbilt University School of Medicine, ; Nashville, 37203 TN USA
                [66 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Department of Population and Quantitative Health Sciences, , Case Western Reserve University, ; Cleveland, 44106 OH USA
                [67 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Division of General Internal Medicine, Department of Medicine, , Johns Hopkins University School of Medicine, ; Baltimore, 21287 MD USA
                [68 ]ISNI 0000 0004 1936 8438, GRID grid.266539.d, Dean’s Office, , University of Kentucky College of Public Health, ; Lexington, 40536 KY USA
                [69 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Human Genome Sequencing Center, , Baylor College of Medicine, ; Houston, 77030 TX USA
                [70 ]ISNI 0000 0001 1941 4308, GRID grid.5133.4, Department of Medical Sciences, , University of Trieste, ; Trieste, 34137 Italy
                [71 ]ISNI 0000 0004 0397 2876, GRID grid.8241.f, Ninewells Hospital & Medical School, , University of Dundee, ; Dundee, DD1 9SY Scotland UK
                [72 ]ISNI 0000000089452978, GRID grid.10419.3d, Clinical Epidemiology, , Leiden University Medical Center, ; Leiden, 2300 RC Netherlands
                [73 ]ISNI 0000 0000 8631 5388, GRID grid.45202.31, Department of Medicine, Faculty of Medicine, , University of Kelaniya, ; Ragama, 11600 Sri Lanka
                [74 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, , Wake Forest School of Medicine, ; Winston-Salem, 27157 NC USA
                [75 ]ISNI 0000 0004 1936 9094, GRID grid.40263.33, Department of Family Medicine and Epidemiology, , Alpert Medical School of Brown University, ; Providence, 02860 RI USA
                [76 ]ISNI 0000 0004 1937 0538, GRID grid.9619.7, Braun School of Public Health, , Hebrew University-Hadassah Medical Center, ; Jerusalem, 91120 Israel
                [77 ]GRID grid.468222.8, Department of Epidemiology, Human Genetics & Environmental Sciences, School of Public Health, , The University of Texas Health Science Center at Austin, ; Austin, 78712 TX USA
                [78 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Department of Genetics, School of Medicine, , Mashhad University of Medical Sciences, ; Mashhad, 91778-99191 Iran
                [79 ]ISNI 0000 0000 9889 6335, GRID grid.413106.1, Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, , Chinese Academy of Medical Sciences and Peking Union Medical College, ; Beijing, 100006 China
                [80 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, , National Institutes of Health, ; Bethesda, 20892 MD USA
                [81 ]ISNI 0000 0001 2217 8588, GRID grid.265219.b, Epidemiology, Tulane University School of Public Health and Tropical Medicine, ; New Orleans, 70112 LA USA
                [82 ]ISNI 0000 0001 2217 8588, GRID grid.265219.b, Medicine, Tulane University School of Medicine, ; New Orleans, 70112 LA USA
                [83 ]ISNI 0000 0001 0726 2490, GRID grid.9668.1, Institute of Biomedicine, School of Medicine, , University of Eastern Finland, ; Kuopio Campus, 70211 Finland
                [84 ]ISNI 0000 0001 0726 2490, GRID grid.9668.1, Institute of Clinical Medicine, Internal Medicine, , University of Eastern Finland, ; Kuopio, 70210 Finland
                [85 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Paediatrics, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, 119228 Singapore
                [86 ]ISNI 0000 0004 0451 6143, GRID grid.410759.e, Khoo Teck Puat—National University Children’s Medical Institute, , National University Health System, ; Singapore, 119228 Singapore
                [87 ]ISNI 0000 0001 2193 0096, GRID grid.223827.e, Division of Epidemiology, Department of Internal Medicine, , University of Utah, ; Salt Lake City, 84132 UT USA
                [88 ]Department of Genetic Medicine, Weill Cornell Medicine, Doha, 24144 Qatar
                [89 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Radiology and Nuclear Medicine, , Erasmus University Medical Center, ; Rotterdam, 3015 GD The Netherlands
                [90 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Department of Ophthalmology, Medical Faculty Mannheim, , University Heidelberg, ; Mannheim, 68167 Germany
                [91 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Hospital, , Capital Medical University, ; Beijing, 100730 China
                [92 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Health Services and Systems Research, , Duke-NUS Medical School, ; Singapore, 169857 Singapore
                [93 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, Institute of Social and Preventive Medicine, , Lausanne University Hospital, ; Lausanne, 1010 Switzerland
                [94 ]ISNI 0000000122986657, GRID grid.34477.33, Cardiovascular Health Research Unit, Medicine, , University of Washington, ; Seattle, 98101 WA USA
                [95 ]ISNI 0000000106344187, GRID grid.265892.2, Division of Preventive Medicine, Department of Medicine, , University of Alabama at Birmingham, School of Medicine, ; Birmingham, 35294 AL USA
                [96 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Ophthalmology, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, 117597 Singapore
                [97 ]ISNI 0000 0000 9136 933X, GRID grid.27755.32, Center for Public Health Genomics, , University of Virginia School of Medicine, ; Charlottesville, 22908 VA USA
                [98 ]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Institute of Human Genetics, , Helmholtz Zentrum München, German Research Center for Environmental Health, ; Neuherberg, 85764 Germany
                [99 ]ISNI 0000000123222966, GRID grid.6936.a, Institute of Human Genetics, , Technische Universität München, ; Munich, 80333 Germany
                [100 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, , VU University Medical Center, ; Amsterdam, 1081 HV The Netherlands
                [101 ]ISNI 0000 0001 1034 1720, GRID grid.410711.2, Department of Genetics, , University of North Carolina, ; Chapel Hill, 27514 NC USA
                [102 ]ISNI 0000 0001 2169 2489, GRID grid.251313.7, Geriatrics, Medicine, , University of Mississippi, ; Jackson, 39216 MS USA
                [103 ]ISNI 0000 0004 1936 7291, GRID grid.7107.1, The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, , University of Aberdeen, ; Aberdeen, AB25 2ZD UK
                [104 ]ISNI 0000 0000 9372 4913, GRID grid.419475.a, Molecular Genetics Section, Laboratory of Neurogenetics, , National Institute on Aging, ; Bethesda, 20892 MD USA
                [105 ]Data Tecnica International, Glen Echo, 20812 MD USA
                [106 ]ISNI 0000 0004 1936 8411, GRID grid.9918.9, Department of Cardiovascular Sciences, , University of Leicester, ; Leicester, LE3 9PQ UK
                [107 ]ISNI 0000 0004 0400 6581, GRID grid.412925.9, NIHR Leicester Biomedical Research Centre, , Glenfield Hospital, ; Leicester, LE3 9QD UK
                [108 ]ISNI 0000000122986657, GRID grid.34477.33, Cardiovascular Health Research Unit, Division of Cardiology, , University of Washington, ; Seattle, 98101 WA USA
                [109 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Department of Epidemiology, , University of Colorado Denver, ; Aurora, 80045 CO USA
                [110 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Division of Endocrinology, Diabetes, and Nutrition, , University of Maryland School of Medicine, ; Baltimore, 21201 MD USA
                [111 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, Program for Personalized and Genomic Medicine, , University of Maryland School of Medicine, ; Baltimore, 21201 MD USA
                [112 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Department of Biochemistry, , Wake Forest School of Medicine, ; Winston-Salem, 27157 NC USA
                [113 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Epidemiology Branch, National Heart, Lung, and Blood Institute, , National Institutes of Health, ; Bethesda, 20892 MD USA
                [114 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Neuherberg, 85764 Germany
                [115 ]ISNI 0000 0004 0644 1675, GRID grid.38603.3e, Department of Public Health, Department of Medicine, , University of Split, ; Split, 21000 Croatia
                [116 ]Psychiatric Hospital “Sveti Ivan”, Zagreb, 10000 Croatia
                [117 ]Gen-Info Ltd., 10000, Zagreb, Croatia
                [118 ]ISNI 0000 0004 0628 215X, GRID grid.410552.7, Department of Clinical Physiology and Nuclear Medicine, , Turku University Hospital, ; Turku, 20521 Finland
                [119 ]ISNI 0000 0001 2097 1371, GRID grid.1374.1, Research Centre of Applied and Preventive Cardiovascular Medicine, , University of Turku, ; Turku, 20520 Finland
                [120 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Institute for Human Genetics, Department of Epidemiology and Biostatistics, , University of California, ; San Francisco, 94143 CA USA
                [121 ]ISNI 0000 0004 1936 8294, GRID grid.214572.7, Department of Epidemiology and Medicine, , University of Iowa, ; Iowa City, 52242 IA USA
                [122 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, , University of Edinburgh, ; Edinburgh, EH16 4UX UK
                [123 ]ISNI 0000000419368657, GRID grid.17635.36, Division of Epidemiology & Community Health, School of Public Health, , University of Minnesota, ; Minneapolis, 55454 MN USA
                [124 ]ISNI 0000 0004 0615 7519, GRID grid.488833.c, Kaiser Permanente Washington, Health Research Institute, ; Seattle, 98101 WA USA
                [125 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Alzheimer Scotland Dementia Research Centre, , The University of Edinburgh, ; Edinburgh, EH8 9JZ UK
                [126 ]ISNI 0000 0004 0483 2525, GRID grid.4567.0, Institute of Genetic Epidemiology, Helmholtz Zentrum München, , German Research Center for Environmental Health, ; Neuherberg, 85764 Germany
                [127 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Institute of Medical Informatics Biometry and Epidemiology, , Ludwig-Maximilians-Universitat Munchen, ; Munich, 81377 Germany
                [128 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Genetics, , Stanford University, ; Stanford, 94305 CA USA
                [129 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Laboratory Medicine and Pathology, , University of Minnesota, ; Minneapolis, 55455 MN USA
                [130 ]ISNI 0000 0001 1013 0499, GRID grid.14758.3f, Public Health Solutions, , National Institute for Health and Welfare, ; Helsinki, 00271 Finland
                [131 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, Diabetes Research Group, , King Abdulaziz University, ; Jeddah, 21589 Saudi Arabia
                [132 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Internal Medicine, , Erasmus University Medical Center, ; Rotterdam, 3015 CE The Netherlands
                [133 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Public Health & Clinical Medicine, , Umeå University, ; Umeå, 90185 Västerbotten Sweden
                [134 ]ISNI 0000 0001 0671 8898, GRID grid.257990.0, Jackson Heart Study, School of Public Health, , Jackson State University, ; Jackson, 39213 MS USA
                [135 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, , Shanghai Jiaotong University School of Medicine, ; Shanghai, 200000 China
                [136 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Epidemiology, Graduate School of Public Health, , University of Pittsburgh, ; Pittsburgh, 15261 PA USA
                [137 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Division of Cancer Control and Population Sciences, , UPMC Hillman Cancer, University of Pittsburgh, ; Pittsburgh, 15232 PA USA
                [138 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, , National Institutes of Health, ; Baltimore, 21224 MD USA
                [139 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, Psychology, The University of Edinburgh, ; Edinburgh, EH8 9JZ UK
                [140 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, MRC-PHE Centre for Environment and Health, , Imperial College London, ; London, W2 1PG UK
                [141 ]GRID grid.66859.34, Broad Institute of the Massachusetts Institute of Technology and Harvard University, ; Boston, 02142 MA USA
                [142 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Section on Nephrology, Department of Internal Medicine, , Wake Forest School of Medicine, ; Winston-Salem, 27157 NC USA
                [143 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Genomics of Common Disease, , Imperial College London, ; London, W12 0NN UK
                [144 ]GRID grid.452622.5, German Center for Diabetes Research (DZD e.V.), ; Neuherberg, 85764 Germany
                [145 ]ISNI 0000 0004 0628 207X, GRID grid.410705.7, Department of Clinical Physiology and Nuclear Medicine, , Kuopio University Hospital, ; Kuopio, 70210 Finland
                [146 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Psychiatry, University of Groningen, , University Medical Center Groningen, ; Groningen, 9713 GZ The Netherlands
                [147 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Genetics, University of Groningen, , University Medical Center Groningen, ; Groningen, 9700 RB The Netherlands
                [148 ]GRID grid.411737.7, Durrer Center for Cardiogenetic Research, , ICIN-Netherlands Heart Institute, ; Utrecht, 1105 AZ The Netherlands
                [149 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Endocrinology, University of Groningen, , University Medical Center Groningen, ; Groningen, 9713 GZ The Netherlands
                [150 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, Internal Medicine, Department of Medicine, , Lausanne University Hospital, ; Lausanne, 1011 Switzerland
                [151 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Public Health Sciences, , Wake Forest School of Medicine, ; Winston-Salem, 27157 NC USA
                [152 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard T. H. Chan School of Public Health, Department of Nutrition, , Harvard University, ; Boston, 02115 MA USA
                [153 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, OCDEM, Radcliffe Department of Medicine, , University of Oxford, ; Oxford, OX3 7LE UK
                [154 ]ISNI 0000 0004 0640 0021, GRID grid.14013.37, Faculty of Medicine, , University of Iceland, ; Reykjavik, 101 Iceland
                [155 ]ISNI 0000 0004 0459 1231, GRID grid.412860.9, Public Health Sciences, Epidemiology and Prevention, , Wake Forest University Health Sciences, ; Winston-Salem, 27157 NC USA
                [156 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Department of Medicine, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, 119228 Singapore
                [157 ]ISNI 0000 0004 1937 0407, GRID grid.410721.1, Cardiology, Medicine, , University of Mississippi Medical Center, ; Jackson, 39216 MS USA
                [158 ]ISNI 0000000089452978, GRID grid.10419.3d, Public Health and Primary Care, , Leiden University Medical Center, ; Leiden, 2300 RC The Netherlands
                [159 ]ISNI 0000000122986657, GRID grid.34477.33, Fred Hutchinson Cancer Research Center, , University of Washington School of Public Health, ; Seattle, 98109 WA USA
                [160 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Biostatistics, Preventive Medicine, , University of Southern California, ; Los Angeles, 90032 CA USA
                [161 ]ISNI 0000000122986657, GRID grid.34477.33, Cardiovascular Health Research Unit, Epidemiology, Medicine and Health Services, , University of Washington, ; Seattle, 98101 WA USA
                [162 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Biostatistics, , University of Washington, ; Seattle, 98105 WA USA
                [163 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine and Dentistry, , Queen Mary University of London, Charterhouse Square, ; London, EC1M 6BQ UK
                [164 ]NHLBI Framingham Heart Study, Framingham, 01702 MA USA
                [165 ]Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, 10029 NY USA
                [166 ]Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute, New York, 10029 NY USA
                [167 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Internal Medicine, Division of Nephrology, University of Groningen, , University Medical Center Groningen, ; Groningen, 9713 GZ The Netherlands
                [168 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, Department of Medical Biology, University of Groningen, , University Medical Center Groningen, ; Groningen, 9713 GZ The Netherlands
                Author information
                http://orcid.org/0000-0002-0827-9101
                http://orcid.org/0000-0001-9667-9406
                http://orcid.org/0000-0003-0247-902X
                http://orcid.org/0000-0003-0907-2548
                http://orcid.org/0000-0002-4689-325X
                http://orcid.org/0000-0003-0129-9860
                http://orcid.org/0000-0002-0703-0742
                http://orcid.org/0000-0002-3071-7278
                http://orcid.org/0000-0002-4176-2947
                http://orcid.org/0000-0002-8532-5087
                Article
                8008
                10.1038/s41467-018-08008-w
                6342931
                30670697
                fa705e93-bb4f-44bd-b9af-819d70b81cb8
                © The Author(s) 2019

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                : 6 June 2018
                : 7 December 2018
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