Article | Published:

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Nature Genetics volume 43, pages 940947 (2011) | Download Citation

Abstract

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10−8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

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Acknowledgements

The Age, Gene/Environment Susceptibility (AGES) Reykjavik Study was funded by US National Institutes of Health (NIH) contract N01-AG-12100, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).

The Old Order Amish Studies were supported by grants and contracts from the NIH including R01 AG18728 (Amish Longevity Study), R01 HL088119 (Amish Calcification Study), U01 GM074518-04 (The Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) study) and U01 HL072515-06 (the Heredity and Phenotype Intervention (HAPI) heart study), the University of Maryland General Clinical Research Center grant M01 RR 16500, the Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center and the Paul Beeson Physician Faculty Scholars in Aging Program. We thank our Amish research volunteers for their long-standing partnership in research and the research staff at the Amish Research Clinic for their hard work and dedication.

The Atherosclerosis Risk in Communities Study (ARIC) was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and US National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Study infrastructure was partly supported by grant number UL1RR025005, a component of the US National Institutes of Health and NIH Roadmap for Medical Research.

The Erasmus Rucphen Family Study was supported by grants from The Netherlands Organisation for Scientific Research, Erasmus Medical Center and the Centre for Medical Systems Biology (CMSB). We are grateful to all study participants and their relatives, the general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection.

The Cardiovascular Health Study research reported in this article was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI grants HL080295, HL075366, HL087652, HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the National Institute of Aging. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00069 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.

The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the US National Institutes of Health and Boston University School of Medicine was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278) and by grants from the National Institute of Neurological Disorders and Stroke (NS17950, P.A.W.) and the National Institute of Aging (AG08122, AG16495, P.A.W. and AG033193, S.S.). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project.

Rotterdam Study I and II (RS I and RS II): The Rotterdam GWAS was funded by the Netherlands Organisation of Scientific Research (NWO, De Nederlandse Organisatie voor Wetenschappelijk Onderzoek) Investments (number 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project number 050-060-810. This study was further supported by an NWO grant (vici, 918-76-619). The Rotterdam Study was funded by the Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are very grateful to the participants and staff from the Rotterdam Study, the participating general practioners and the pharmacists. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS database. We would like to thank T.A. Knoch, L.V. de Zeeuw, A. Abuseiris and R. de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the National German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministeriumfuer Forschung und Technology under grants #01 AK 803 A-H and #01 IG 07015 G, for access to their grid resources.

The SardiNIA Study: This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. The SardiNIA ('Progenia') team was supported by Contract NO1-AG-1–2109 from the National Institute on Aging. The efforts of G.R.A. were supported in part by contract 263-MA-410953 from the National Institute on Aging to the University of Michigan and by research grants HG005581 and HL084729 from the National Institutes of Health (to G.R.A.).

We thank M. Piseddu, Bishop of Ogliastra; E. Lai and his administration in Lanusei for providing and furnishing the clinic site; the mayors of Ilbono, Arzana and Elini; the head of the local Public Health Unit Ar1; and the residents of the towns for their volunteerism and cooperation. We also thank H. Spurgeon and P. Pullen for invaluable help with equipment and readings and M. Evans and D. Longo for helpful discussions.

The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants number 01ZZ9603, 01ZZ0103 and 01ZZ0403), and the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to the contribution of A. Teumer, A. Hoffmann and A. Petersmann in generating the SNP data. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG.

The Austrian Stroke Prevention Study (ASPS): The research reported in this article was funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supports the databank of the ASPS.

The Coronary Artery Progression Study: Research leading these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 201668; AtheroRemo.

The Gutenberg Heart Study was funded through the government of Rheinland-Pfalz ('Stiftung Rheinland Pfalzfür Innovation', contract number AZ 961-386261/733), the research programs 'Wissenschafft Zukunft' and 'Schwerpunkt Vaskuläre Prävention' of the Johannes Gutenberg-University of Mainz and its contract with BoehringerIngelheim and Philips Medical Systems, including an unrestricted grant for the Gutenberg Heart Study. Specifically, the research reported in this article was supported by the National Genome Network 'NGFNplus' (contract number project A3 01GS0833) by the Federal Ministry of Education and Research, Germany.

Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNplus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of Ludwig-Maximilians-Universität Munich (LMU) innovative. IMT measurement of the KORA cohort was funded by a grant of the Karl-Wilder Foundation. Finally, part of this work was financed by the German Diabetes Center, which is funded by the German Federal Ministry of Health and the Ministry of Innovation, Science, Research and Technology of the State of North Rhine Westphalia.

The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of L. Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney.

The Cardiovascular Risk in Young Finns Study was supported by the Academy of Finland (grant numbers 117797, 121584 and 126925), the Social Insurance Institution of Finland, University Hospital Medical funds to Tampere, and Turku University Hospitals, the Finnish Foundation of Cardiovascular Research.

CARDIoGRAM: We acknowledge the contributions of all of the authors of the CARDIoGRAM report, as listed in their primary analysis publication14.

Author information

Author notes

    • Joshua C Bis
    • , Maryam Kavousi
    • , Nora Franceschini
    • , Aaron Isaacs
    • , Gonçalo R Abecasis
    • , Ulf Schminke
    • , Wendy S Post
    • , Albert V Smith
    • , L Adrienne Cupples
    • , Anne B Newman
    • , Jacqueline Witteman
    • , Gerardo Heiss
    • , Cornelia van Duijn
    • , Angelo Scuteri
    • , Georg Homuth
    • , Braxton D Mitchell
    • , Vilmundur Gudnason
    •  & Christopher J O'Donnell

    These authors contributed equally to this work.

Affiliations

  1. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
    •  & Bruce M Psaty
  2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Maryam Kavousi
    • , Abbas Dehghan
    • , Andre Uitterlinden
    • , Albert Hofman
    •  & Jacqueline Witteman
  3. Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, The Netherlands.

    • Maryam Kavousi
    • , Abbas Dehghan
    • , Fernando Rivadeneira
    • , Andre Uitterlinden
    • , Albert Hofman
    • , Jacqueline Witteman
    •  & Cornelia van Duijn
  4. Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
    • , Xia Li
    •  & Gerardo Heiss
  5. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Aaron Isaacs
    •  & Cornelia van Duijn
  6. Centre for Medical Systems Biology, Leiden, The Netherlands.

    • Aaron Isaacs
    • , Ben Oostra
    •  & Cornelia van Duijn
  7. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

    • Gonçalo R Abecasis
  8. Department of Neurology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Ulf Schminke
  9. Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

    • Wendy S Post
  10. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith
    • , Bolli Thorsson
    • , Thor Aspelund
    • , Gudny Eiriksdottir
    •  & Vilmundur Gudnason
  11. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • L Adrienne Cupples
    • , Serkalem Demissie
    •  & Charles C White
  12. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • L Adrienne Cupples
    • , Caroline S Fox
    • , Philip A Wolf
    •  & Christopher J O'Donnell
  13. Centre for Clinical Neuroscience, St. George's University of London, London, UK.

    • Hugh S Markus
    •  & Steve Bevan
  14. Department of Neurology, Medical University Graz, Graz, Austria.

    • Reinhold Schmidt
    •  & Eva-Maria Stoegerer
  15. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland.

    • Jennifer E Huffman
    •  & Caroline Hayward
  16. Department of Clinical Chemistry, University of Tampere, Tampere, Finland.

    • Terho Lehtimäki
  17. Tampere University Hospital, Tampere, Finland.

    • Terho Lehtimäki
    •  & Mika Kähönen
  18. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Jens Baumert
    •  & Christa Meisinger
  19. Department of Medicine 2, University Medical Center Mainz, Mainz, Germany.

    • Thomas Münzel
    • , Renate B Schnabel
    • , Philipp S Wild
    • , Tanja Zeller
    •  & Stefan Blankenberg
  20. Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Susan R Heckbert
  21. Group Health Research Institute, Group Health, Seattle, Washington, USA.

    • Susan R Heckbert
    •  & Bruce M Psaty
  22. Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Kari North
  23. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Ben Oostra
  24. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

    • Olli Raitakari
  25. Department of Clinical Physiology, Turku University Hospital, Turku, Finland.

    • Olli Raitakari
  26. Institute for Medical Biometry and Statistics, University of Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

    • Arne Schillert
    •  & Andreas Ziegler
  27. Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.

    • Serena Sanna
    • , Marco Orru
    • , Gianluca Usala
    •  & Manuela Uda
  28. Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Henry Völzke
  29. Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Yu-Ching Cheng
  30. Division of Endocrinology, Metabolism, and Diabetes, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox
  31. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • Kenneth Rice
  32. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Fernando Rivadeneira
    •  & Andre Uitterlinden
  33. Baylor College of Medicine, Houston, Texas, USA.

    • Vijay Nambi
    •  & Christie Ballantyne
  34. Center for Cardiovascular Prevention, The Methodist DeBakey Heart and Vascular Center, Houston, Texas, USA.

    • Vijay Nambi
  35. Ben Taub General Hospital, Houston, Texas, USA.

    • Vijay Nambi
  36. The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv, Israel.

    • Eran Halperin
  37. The International Computer Science Institute, Berkeley, California, USA.

    • Eran Halperin
  38. Department of Neurology, General Hospital and Medical University Graz, Graz, Austria.

    • Katja E Petrovic
  39. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Leena Peltonen
  40. Institute for Molecular Medicine Finland, Biomedicum, University of Helsinki and National Institute for Health and Welfare, Helsinki, Finland.

    • Leena Peltonen
  41. Institute of Epidemiology I, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • H Erich Wichmann
  42. Department of Internal Medicine B, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Marcus Dörr
  43. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Afshin Parsa
    • , Alan R Shuldiner
    •  & Braxton D Mitchell
  44. University of Iceland, Reykjavik, Iceland.

    • Thor Aspelund
    •  & Vilmundur Gudnason
  45. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  46. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Sekar Kathiresan
  47. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Sekar Kathiresan
  48. The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Muredach P Reilly
  49. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Kent Taylor
    •  & Jerome I Rotter
  50. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • David J Couper
  51. Department of Neurology, Klinikum Herford, Herford, Germany.

    • Matthias Sitzer
  52. Department of Clinical Physiology, University of Tampere, Tampere, Finland.

    • Mika Kähönen
  53. Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.

    • Thomas Illig
    •  & Norman Klopp
  54. Biobank of the Hannover Medical School, Hannover Medical School, Hannover, Germany.

    • Thomas Illig
  55. Cardiology Operating Unit, Division of Medicine, Santa Barbara Hospital, Iglesias, Italy.

    • Marco Orru
  56. Institute of Clinical Chemistry and Laboratory Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Jan Lüdemann
  57. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  58. Ludwig-Maximilians University of Munich, Medical Clinic Innenstadt, Diabetes Center, Munich, Germany.

    • Jochen Seissler
  59. Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.

    • Florian Ernst
    • , Ravi Kumar Chilukoti
    •  & Georg Homuth
  60. Intramural Research Program, Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

    • Lenore J Launer
    •  & Tamara B Harris
  61. Department Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.

    • Ralph B D'Agostino Sr
  62. St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • Daniel H O'Leary
  63. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.

    • Joachim Thiery
  64. Leipzig Research Center of Civilization Diseases, Medical Faculty, University of Leipzig, Leipzig, Germany.

    • Joachim Thiery
  65. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA.

    • Edward G Lakatta
    •  & Angelo Scuteri
  66. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Philip A Wolf
  67. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  68. Department of Health Services, University of Washington, Seattle, Washington, USA.

    • Bruce M Psaty
  69. Department of Radiology, Tufts University School of Medicine, Boston, Massachusetts, USA.

    • Joseph F Polak
  70. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

    • Wolfgang Rathmann
  71. University of Texas, School of Public Health, Human Genetics Center, Houston, Texas, USA.

    • Eric Boerwinkle
  72. Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.

    • Helena Schmidt
  73. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland.

    • James F Wilson
  74. Department of Medicine, University of Turku, Turku, Finland.

    • Jorma Viikari
  75. Turku University Hospital, Turku, Finland.

    • Jorma Viikari
  76. Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany.

    • Wolfgang Koenig
  77. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Anne B Newman
  78. Department of Epidemiology & Public Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Braxton D Mitchell
  79. Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts, USA.

    • Christopher J O'Donnell

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  1. the CARDIoGRAM Consortium

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Contributions

Study concept and design: J.C.B., M. Kavousi, N.F., G.R.A., L.A.C., T.L., S.R.H., K.N., C.H., O.R., C.S.F., V.N., R.B.S., T.A., M.S., M. Kähönen, P.S.W., A.R.S., J.I.R., J.S., D.H.O., E.G.L., B.M.P., M.U., E.B., J.V., W.K., S. Blankenberg, A.B.N., J.W., C.v.D., A. Scuteri, V.G., C.J.O.

Acquisition of the data: J.C.B., A.I., G.R.A., U.S., W.S.P., H.S.M., R.S., T.L., B.O., S. Bevan, E.-M.S., O.R., C.M., H.V., B.T., F.R., K.E.P., H.E.W., R.B.S., M.D., A.P., T.A., S.K., M.P.R., K.T., A.U., M.S., M. Kähönen, T.I., P.S.W., M.O., J.L., A.R.S., G.E., J.I.R., A.H., J.S., T.Z., G.U., F.E., L.J.L., R.B.D., D.H.O., J.T., T.B.H., P.A.W., B.M.P., J.F.P., W.R., E.B., N.K., H.S., J.F.W., J.V., W.K., S. Blankenberg, A.B.N., G. Heiss, C.v.D., A. Scuteri, G. Homuth, B.D.M., V.G., C.J.O.

Statistical analysis and interpretation of the data: J.C.B., M. Kavousi, N.F., A.I., G.R.A., A.V.S., L.A.C., J.E.H., T.L., J.B., S.R.H., A.D., K.N., C.H., O.R., A. Schillert, S.S., Y.-C.C., K.R., V.N., E.H., K.E.P., T.A., S.D., S.K., P.S.W., C.C.W., R.B.D., A.Z., R.K.C., H.S., C.J.O.

Drafting of the manuscript: J.C.B., M. Kavousi, N.F., A.I., K.N., O.R., M. Kähönen, J.F.P., J.V., C.J.O.

Critical revision of the manuscript: J.C.B., M. Kavousi, N.F., A.I., G.R.A., U.S., W.S.P., L.A.C., H.S.M., R.S., T.L., J.B., T.M., S.R.H., A.D., K.N., O.R., C.M., H.V., B.T., K.R., F.R., V.N., H.E.W., R.B.S., M.D., A.P., S.D., M.P.R., K.T., A.U., D.J.C., M.S., M. Kähönen, T.I., J.L., G.E., J.I.R., A.H., J.S., F.E., L.J.L., R.B.D., D.H.O., C.B., A.Z., E.G.L., R.K.C., T.B.H., B.M.P., J.F.P., X.L., W.R., E.B., J.V., W.K., S. Blankenberg, J.W., C.v.D., A. Scuteri, G. Homuth, B.D.M., V.G., C.J.O.

Obtained funding: G.R.A., U.S., H.S.M., R.S., T.L., O.R., H.V., L.P., M.D., S.K., A.U., M.S., M. Kähönen, P.S.W., A.R.S., J.I.R., A.H., J.S., A.Z., P.A.W., B.M.P., J.F.P., W.R., M.U., E.B., H.S., J.F.W., J.V., W.K., A.B.N., G. Heiss, C.v.D., G. Homuth, B.D.M., V.G., C.J.O.

Competing interests

V.N. has a non-financial research collaboration with General Electric and Medipattern Inc.

Corresponding authors

Correspondence to Joshua C Bis or Christopher J O'Donnell.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Tables 1–7 and Supplementary Note.

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DOI

https://doi.org/10.1038/ng.920

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