Article | Published:

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Nature Geneticsvolume 50pages14121425 (2018) | Download Citation

Abstract

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

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Data availability

The genetic and phenotypic UKB data are available upon application to the UK Biobank (https://www.ukbiobank.ac.uk). ICBP summary data can be accessed through request to the ICBP steering committee. Contact the corresponding authors to apply for access to the data. The UKB + ICBP summary GWAS discovery data can be accessed by request to the corresponding authors and will be available via LDHub (http://ldsc.broadinstitute.org/ldhub/). All replication data generated during this study are included in the published article. For example, association results of look-up variants from our replication analyses and the subsequent combined meta-analyses are contained within the Supplementary Tables.

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Acknowledgements

H.R.W. was funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Centre at Barts and The London School of Medicine and Dentistry. D.M.-A. is supported by the Medical Research Council (grant number MR/L01632X.1). B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. C.P.C. was funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Center at Barts and The London School of Medicine and Dentistry. S. Thériault was supported by Canadian Institutes of Health Research; Université Laval (Quebec City, Canada). G.P. was supported by Canada Research Chair in Genetic and Molecular Epidemiology and CISCO Professorship in Integrated Health Biosystems. I. Karaman was supported by the EU PhenoMeNal project (Horizon 2020, 654241). C.P.K. is supported by grant U01DK102163 from the NIH-NIDDK and by resources from the Memphis VA Medical Center. S.D. was supported for this work by grants from the European Research Council (ERC), the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Agence Nationale de la Recherche (ANR). T. Boutin, J. Marten, V.V., A.F.W. and C.H. were supported by a core MRC grant to the MRCHGU QTL in Health and Disease research programme. M. Boehnke is supported by NIH grant R01-DK062370. H.W. and A. Goel acknowledge support of the Tripartite Immunometabolism Consortium (TrIC), Novo Nordisk Foundation (grant NNF15CC0018486). N.V. was supported by a Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. C. Menni is funded by the MRC AimHy (MR/M016560/1) project grant. M.A.N.’s participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH. M. Brumat, M. Cocca, I.G., P.G., G.G., A. Morgan, A.R., D.V., C.M.B., C.F.S., M. Traglia and D.T. were supported by Italian Ministry of Health grant RF2010 to P.G. and RC2008 to P.G. D.I.B. is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635). J.C.C. is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). C.P.C., P.B.M. and M.R.B. were funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Centre at Barts. T.F. is supported by the NIHR Biomedical Research Centre, Oxford. M.R. is the recipient of an award from China Scholarship Council (No. 2011632047). C.L. was supported by the Medical Research Council UK (G1000143, MC_UU_12015/1, MC_PC_13048 and MC_U106179471), Cancer Research UK (C864/A14136) and EU FP6 programme (LSHM_CT_2006_037197). G.B.E. is supported by the Swiss National Foundation SPUM project FN 33CM30-124087, Geneva University, and the Fondation pour Recherches Médicales, Genève. C.M.L.is supported by the Li Ka Shing Foundation; WT-SSI/John Fell funds; the NIHR Biomedical Research Centre, Oxford; Widenlife; and NIH (CRR00070 CR00.01). R.J.F.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855 and R01DK107786). D.O.M.-K. is supported by the Dutch Science Organization (ZonMW-VENI Grant 916.14.023). M.M. was supported by the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. H.W. and M.F. acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence (RE/13/1/30181). A. Goel and H.W. acknowledge the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVGenes@Target) and A. Goel the Wellcome Trust Institutional strategic support fund. L.R. was supported by Forschungs- und Förder-Stiftung INOVA, Liechtenstein. M. Tomaszewski is supported by British Heart Foundation (PG/17/35/33001). P. Sever is recipient of an NIHR Senior Investigator Award and is supported by the Biomedical Research Centre Award to Imperial College Healthcare NHS Trust. P.v.d.H. was supported by the ICIN-NHI and Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395). N.J.W. was supported by the Medical Research Council UK (G1000143, MC_UU_12015/1, MC_PC_13048 and MC_U106179471), Cancer Research UK (C864/A14136) and EU FP6 programme (LSHM_CT_2006_037197). E.Z. was supported by the Wellcome Trust (WT098051). J.N.H. was supported by the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) training program, funded by T32CA160056 (PI: X.-O. Shu) and by VA grant 1I01CX000982. A. Giri was supported by VA grant 1I01CX000982. T.L.E. and D.R.V.E. were supported by grant R21HL121429 from NHLBI, NIH. A.M.H. was supported by VA Award #I01BX003360. C.J.O. was supported by VA Boston Healthcare, Section of Cardiology and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School. The MRC/BHF Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194) and UK National Institute for Health Research Cambridge Biomedical Research Centre. J. Danesh is a British Heart Foundation Professor and NIHR Senior Investigator. L.V.W. holds a GlaxoSmithKline/British Lung Foundation Chair in Respiratory Research. P.E. acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141), and the Medical Research Council (MRC) and Public Health England (PHE) Centre for Environment and Health (MR/L01341X/1). P.E. is a UK Dementia Research Institute (DRI) professor at Imperial College London, funded by the MRC, Alzheimer’s Society and Alzheimer’s Research UK. He is also associate director of Health Data Research–UK London, funded by a consortium led by the Medical Research Council. M.J.C. was funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Center at Barts and The London School of Medicine and Dentistry. M.J.C. is a National Institute for Health Research (NIHR) senior investigator, and this work is funded by the MRC eMedLab award to M.J.C. and M.R.B. and by the NIHR Biomedical Research Centre at Barts.

This research has been conducted using the UK Biobank Resource under application numbers 236 and 10035. This research was supported by the British Heart Foundation (grant SP/13/2/30111). Large-scale comprehensive genotyping of UK Biobank for cardiometabolic traits and diseases: UK CardioMetabolic Consortium (UKCMC).

Computing: This work was enabled using the computing resources of (i) the UK Medical Bioinformatics aggregation, integration, visualisation and analysis of large, complex data (UK Med-Bio), which is supported by the Medical Research Council (grant number MR/L01632X/1), and (ii) the MRC eMedLab Medical Bioinformatics Infrastructure, supported by the Medical Research Council (grant number MR/L016311/1). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. C.P.K. is an employee of the US Department of Veterans Affairs. Opinions expressed in this paper are those of the authors and do not necessarily represent the opinion of the Department of Veterans Affairs or the United States Government.

Author information

Author notes

  1. These authors contributed equally: Evangelos Evangelou, Helen R. Warren, David Mosen-Ansorena, Borbala Mifsud, Raha Pazoki, He Gao, Georgios Ntritsos, Niki Dimou, Ioanna Tzoulaki, Michael R. Barnes, Louise V. Wain, Paul Elliott, Mark J. Caulfield.

  2. A consortium acknowledgement and affiliations for the Million Veteran Program are included in Supplementary Note 2.

Affiliations

  1. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    • Evangelos Evangelou
    • , David Mosen-Ansorena
    • , Raha Pazoki
    • , He Gao
    • , Ibrahim Karaman
    • , Marina Evangelou
    • , John C. Chambers
    • , Marjo-Riitta Jarvelin
    • , Benjamin Lehne
    • , Anne-Claire Vergnaud
    • , Weihua Zhang
    • , Ioanna Tzoulaki
    •  & Paul Elliott
  2. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece

    • Evangelos Evangelou
    • , Georgios Ntritsos
    • , Niki Dimou
    •  & Ioanna Tzoulaki
  3. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    • Helen R. Warren
    • , Borbala Mifsud
    • , Claudia P. Cabrera
    • , Fu Liang Ng
    • , Katarzyna Witkowska
    • , Evan Tzanis
    • , Patricia B. Munroe
    • , Morris J. Brown
    • , Michael R. Barnes
    •  & Mark J. Caulfield
  4. National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Queen Mary University of London, London, UK

    • Helen R. Warren
    • , Claudia P. Cabrera
    • , Patricia B. Munroe
    • , Morris J. Brown
    • , Michael R. Barnes
    •  & Mark J. Caulfield
  5. MRC-PHE Centre for Environment and Health, Imperial College London, London, UK

    • He Gao
    • , John C. Chambers
    • , Marjo-Riitta Jarvelin
    • , Jaspal S. Kooner
    • , Ioanna Tzoulaki
    •  & Paul Elliott
  6. Department of Mathematics, Imperial College London, London, UK

    • Marina Evangelou
  7. Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA

    • Jacklyn N. Hellwege
    •  & Todd L. Edwards
  8. Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center; Tennessee Valley Health Systems VA, Nashville, TN, USA

    • Ayush Giri
    •  & Digna R. Velez Edwards
  9. Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA

    • Yan V. Sun
  10. Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA

    • Yan V. Sun
  11. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA

    • Kelly Cho
    •  & J. Michael Gaziano
  12. Division of Aging, Department of Medicine, Brigham and Women’s Hospital; Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Kelly Cho
    •  & J. Michael Gaziano
  13. Atlanta VAMC and Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA

    • Peter W. F. Wilson
  14. VA Palo Alto Health Care System, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Philip S. Tsao
  15. Nephrology Section, Memphis VA Medical Center and University of Tennessee Health Science Center, Memphis, TN, USA

    • Csaba P. Kovesdy
  16. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Tonu Esko
    • , Reedik Mägi
    • , Lili Milani
    • , Elin Org
    •  & Andres Metspalu
  17. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    • Tonu Esko
    • , Niek Verweij
    •  & Sekar Kathiresan
  18. Department Clinical Sciences, Malmö, Lund University, Malmö, Sweden

    • Peter Almgren
    •  & Olle Melander
  19. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK

    • Thibaud Boutin
    • , Jennifer E. Huffman
    • , Jonathan Marten
    • , Veronique Vitart
    • , James F. Wilson
    • , Alan F. Wright
    •  & Caroline Hayward
  20. Department of Neurology, Bordeaux University Hospital, Bordeaux, France

    • Stéphanie Debette
  21. Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, CHU Bordeaux, Bordeaux, France

    • Stéphanie Debette
    • , Muralidharan Sargurupremraj
    •  & Christophe Tzourio
  22. Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA

    • Jun Ding
    •  & Yong Qian
  23. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Franco Giulianini
    • , Paul M. Ridker
    • , Lynda M. Rose
    •  & Daniel I. Chasman
  24. Hunter Medical Research Institute and Faculty of Health, University of Newcastle, New Lambton Heights, New South Wales, Australia

    • Elizabeth G. Holliday
    • , Christopher Oldmeadow
    • , John R. Attia
    •  & Rodney J. Scott
  25. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    • Anne U. Jackson
    •  & Michael Boehnke
  26. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

    • Ruifang Li-Gao
    • , Renée de Mutsert
    •  & Dennis O. Mook-Kanamori
  27. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Wei-Yu Lin
    • , Praveen Surendran
    • , Adam S. Butterworth
    • , John Danesh
    •  & Joanna M. M. Howson
  28. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK

    • Jian’an Luan
    • , Sara M. Willems
    • , Jing-Hua Zhao
    • , Ruth J. F. Loos
    • , Claudia Langenberg
    • , Robert A. Scott
    •  & Nicholas J. Wareham
  29. Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK

    • Massimo Mangino
    • , Cristina Menni
    •  & Tim D. Spector
  30. NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, UK

    • Massimo Mangino
  31. Wellcome Trust Sanger Institute, Hinxton, UK

    • Bram Peter Prins
    •  & Eleftheria Zeggini
  32. Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, UK

    • Nabi Shah
    • , Alex S. F. Doney
    •  & Colin N. A. Palmer
  33. Department of Pharmacy, COMSATS Institute of Information Technology, Abbottabad, Pakistan

    • Nabi Shah
  34. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada

    • Sébastien Thériault
    •  & Guillaume Paré
  35. Institut universitaire de cardiologie et de pneumologie de Québec–Université Laval, Quebec City, Quebec, Canada

    • Sébastien Thériault
  36. Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    • Niek Verweij
    •  & Sekar Kathiresan
  37. University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands

    • Niek Verweij
  38. University of Lille, Inserm, Centre Hosp. Univ. Lille, Institut Pasteur de Lille, UMR1167 – RID-AGE – Risk factors and molecular determinants of aging-related diseases, Epidemiology and Public Health Department, Lille, France

    • Philippe Amouyel
  39. University of Dundee, Ninewells Hospital & Medical School, Dundee, UK

    • John Connell
  40. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • Martin Farrall
    • , Anuj Goel
    • , Cecilia M. Lindgren
    • , Anubha Mahajan
    • , Andrew P. Morris
    •  & Hugh Watkins
  41. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    • Martin Farrall
    • , Anuj Goel
    •  & Hugh Watkins
  42. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    • Andrew D. Morris
  43. Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

    • Raymond Noordam
  44. Imperial Clinical Trials Unit, London, UK

    • Neil R. Poulter
  45. School of Medicine, University College Dublin, Dublin, Ireland

    • Denis C. Shields
  46. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

    • Alice Stanton
  47. International Centre for Circulatory Health, Imperial College London, London, UK

    • Simon Thom
  48. Center for Statistical Genetics, Department of Biostatistics, SPH II, Washington Heights, Ann Arbor, MI, USA

    • Gonçalo Abecasis
  49. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands

    • Najaf Amin
    • , Ben A. Oostra
    •  & Cornelia M. van Duijn
  50. Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Dan E. Arking
    • , Aravinda Chakravarti
    • , Georg B. Ehret
    •  & Priyanka Nandakumar
  51. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

    • Kristin L. Ayers
    •  & Heather J. Cordell
  52. Sema4, a Mount Sinai venture, Stamford, CT, USA

    • Kristin L. Ayers
  53. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy

    • Caterina M. Barbieri
    • , Cinzia F. Sala
    • , Daniela Toniolo
    •  & Michela Traglia
  54. Department of Health Sciences, University of Leicester, Leicester, UK

    • Chiara Batini
    • , Tineka Blake
    • , A. Mesut Erzurumluoglu
    • , Nick Shrine
    • , Martin D. Tobin
    •  & Louise V. Wain
  55. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

    • Joshua C. Bis
  56. Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland

    • Murielle Bochud
    •  & Zoltan Kutalik
  57. Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston and Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    • Eric Boerwinkle
  58. Department of Biological Psychology, Vrije Universiteit Amsterdam, EMGO+ Institute, VU University Medical Center, Amsterdam, the Netherlands

    • Dorret I. Boomsma
    • , Eco J. de Geus
    • , Jouke-Jan Hottenga
    •  & Gonneke Willemsen
  59. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Erwin P. Bottinger
    • , Ruth J. F. Loos
    •  & Yingchang Lu
  60. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    • Peter S. Braund
    • , Christopher P. Nelson
    •  & Nilesh J. Samani
  61. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK

    • Peter S. Braund
    • , Christopher P. Nelson
    • , Nilesh J. Samani
    •  & Louise V. Wain
  62. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy

    • Marco Brumat
    • , Ilaria Gandin
    • , Paolo Gasparini
    • , Giorgia Girotto
    • , Anna Morgan
    •  & Dragana Vuckovic
  63. Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Archie Campbell
    •  & Sarah E. Harris
  64. Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK

    • Archie Campbell
    •  & Sandosh Padmanabhan
  65. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK

    • Harry Campbell
    • , Peter K. Joshi
    •  & James F. Wilson
  66. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

    • John C. Chambers
  67. Department of Cardiology, Ealing Hospital, Middlesex, UK

    • John C. Chambers
    • , Jaspal S. Kooner
    •  & Weihua Zhang
  68. Imperial College Healthcare NHS Trust, London, UK

    • John C. Chambers
    •  & Jaspal S. Kooner
  69. Centre for Brain Research, Indian Institute of Science, Bangalore, India

    • Ganesh Chauhan
  70. Institute of Genetics and Biophysics “A. Buzzati-Traverso”, CNR, Napoli, Italy

    • Marina Ciullo
    • , Teresa Nutile
    • , Daniela Ruggiero
    •  & Rossella Sorice
  71. IRCCS Neuromed, Pozzilli, Isernia, Italy

    • Marina Ciullo
    •  & Daniela Ruggiero
  72. Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy

    • Massimiliano Cocca
    • , Paolo Gasparini
    • , Giorgia Girotto
    •  & Antonietta Robino
  73. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA

    • Francis Collins
  74. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Gail Davies
    • , Ian J. Deary
    • , Alan J. Gow
    • , Sarah E. Harris
    • , David C. M. Liewald
    • , Lorna M. Lopez
    •  & John M. Starr
  75. Department of Psychology, University of Edinburgh, Edinburgh, UK

    • Gail Davies
    • , Ian J. Deary
    • , David C. M. Liewald
    •  & Alison Pattie
  76. Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Martin H. de Borst
  77. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

    • Joris Deelen
  78. Institute for Biomedicine, Eurac Research, Bolzano, Italy – Affiliated Institute of the University of Lübeck, Lübeck, Germany

    • Fabiola Del Greco M.
    • , Andrew A. Hicks
    •  & Peter P. Pramstaller
  79. Mathematical and Statistical Computing Laboratory, Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA

    • Cumhur Yusuf Demirkale
    • , Peter J. Munson
    •  & Quang Tri Nguyen
  80. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany

    • Marcus Dörr
  81. DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany

    • Marcus Dörr
    • , Alexander Teumer
    •  & Uwe Völker
  82. Cardiology, Department of Medicine, Geneva University Hospital, Geneva, Switzerland

    • Georg B. Ehret
    •  & Li Lin
  83. CIBERCV & Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain

    • Roberto Elosua
    •  & Jaume Marrugat
  84. Faculty of Medicine, Universitat de Vic–Central de Catalunya, Vic, Spain

    • Roberto Elosua
  85. Department of Immunology, Genetics and Pathology, Uppsala Universitet, Science for Life Laboratory, Uppsala, Sweden

    • Stefan Enroth
    • , Ulf Gyllensten
    •  & Åsa Johansson
  86. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

    • Teresa Ferreira
  87. Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK

    • Teresa Ferreira
    •  & Cecilia M. Lindgren
  88. Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden

    • Mattias Frånberg
    • , Anders Hamsten
    •  & Rona J. Strawbridge
  89. Centre for Molecular Medicine, L8:03, Karolinska Universitetsjukhuset, Solna, Sweden

    • Mattias Frånberg
    • , Anders Hamsten
    •  & Rona J. Strawbridge
  90. Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden

    • Mattias Frånberg
  91. Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands

    • Oscar H. Franco
    • , Albert Hofman
    • , André G. Uitterlinden
    •  & Germaine C. Verwoert
  92. Department of Public Health and Caring Sciences, Geriatrics, Uppsala, Sweden

    • Vilmantas Giedraitis
  93. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    • Christian Gieger
  94. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

    • Christian Gieger
    • , Annette Peters
    •  & Janina S. Ried
  95. German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

    • Christian Gieger
    •  & Annette Peters
  96. Department of Psychology, School of Social Sciences, Heriot-Watt University, Edinburgh, UK

    • Alan J. Gow
  97. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Vilmundur Gudnason
    •  & Albert V. Smith
  98. Icelandic Heart Association, Kopavogur, Iceland

    • Vilmundur Gudnason
    •  & Albert V. Smith
  99. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor–UCLA Medical Center, Torrance, CA, USA

    • Xiuqing Guo
    • , Jerome I. Rotter
    • , Kent D. Taylor
    •  & Jie Yao
  100. Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA

    • Tamara B. Harris
    •  & Lenore J. Launer
  101. Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Catharina A. Hartman
  102. Department of Public Health Solutions, National Institute for Health and Welfare (THL), Helsinki, Finland

    • Aki S. Havulinna
    • , Pekka Jousilahti
    • , Antti Jula
    • , Paul Knekt
    • , Seppo Koskinen
    • , Kati Kristiansson
    • , Teemu Niiranen
    • , Markus Perola
    •  & Veikko Salomaa
  103. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • Aki S. Havulinna
    • , Aarno Palotie
    • , Markus Perola
    • , Samuli Ripatti
    •  & Antti-Pekka Sarin
  104. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria

    • Edith Hofer
    •  & Reinhold Schmidt
  105. Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria

    • Edith Hofer
  106. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Albert Hofman
  107. National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    • Jennifer E. Huffman
    • , Shih-Jen Hwang
    • , Roby Joehanes
    • , Andrew D. Johnson
    • , Marty Larson
    •  & Daniel Levy
  108. The Population Science Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    • Jennifer E. Huffman
    •  & Shih-Jen Hwang
  109. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    • Erik Ingelsson
  110. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Erik Ingelsson
  111. Department of Pulmonary Physiology and Sleep, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia, Australia

    • Alan James
  112. School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia

    • Alan James
  113. Department of Psychiatry, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, the Netherlands

    • Rick Jansen
  114. Biocenter Oulu, University of Oulu, Oulu, Finland

    • Marjo-Riitta Jarvelin
  115. Center For Life-course Health Research, University of Oulu, Oulu, Finland

    • Marjo-Riitta Jarvelin
  116. Unit of Primary Care, Oulu University Hospital, Oulu, Oulu, Finland

    • Marjo-Riitta Jarvelin
  117. Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA

    • Roby Joehanes
  118. Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    • Andrew D. Johnson
    •  & Daniel Levy
  119. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

    • J. Wouter Jukema
    •  & Stella Trompet
  120. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland

    • Mika Kähönen
  121. Department of Clinical Physiology, Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland

    • Mika Kähönen
  122. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA

    • Sekar Kathiresan
  123. Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    • Bernard D. Keavney
    •  & Maciej Tomaszewski
  124. Division of Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    • Bernard D. Keavney
    •  & Maciej Tomaszewski
  125. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK

    • Kay-Tee Khaw
  126. Data Science Institute and Lancaster Medical School, Lancaster, UK

    • Joanne Knight
  127. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia

    • Ivana Kolcic
    •  & Ozren Polasek
  128. National Heart and Lung Institute, Imperial College London, London, UK

    • Jaspal S. Kooner
    •  & Peter Sever
  129. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    • Zoltan Kutalik
  130. Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia

    • Maris Laan
    •  & Siim Sõber
  131. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland

    • Terho Lehtimäki
    •  & Leo-Pekka Lyytikäinen
  132. Department of Clinical Chemistry, Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland

    • Terho Lehtimäki
    •  & Leo-Pekka Lyytikäinen
  133. Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden

    • Lars Lind
    •  & Johan Sundström
  134. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • Cecilia M. Lindgren
    •  & Christopher Newton-Cheh
  135. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    • YongMei Liu
  136. Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Ruth J. F. Loos
  137. Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland

    • Lorna M. Lopez
  138. University College Dublin, UCD Conway Institute, Centre for Proteome Research, UCD, Belfield, Dublin, Ireland

    • Lorna M. Lopez
  139. Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK

    • Chrysovalanto Mamasoula
  140. Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical Center/GGZ inGeest, Amsterdam, the Netherlands

    • Yuri Milaneschi
    •  & Brenda W. J. H. Penninx
  141. Department of Biostatistics, University of Liverpool, Liverpool, UK

    • Andrew P. Morris
  142. Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA

    • Alanna C. Morrison
  143. Data Tecnica International, Glen Echo, MD, USA

    • Mike A. Nalls
  144. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA

    • Mike A. Nalls
  145. Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland

    • Teemu Niiranen
  146. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Ilja M. Nolte
    • , Harold Snieder
    • , Ahmad Vaez
    •  & Peter J. van der Most
  147. Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Albertine J. Oldehinkel
    •  & Harriëtte Riese
  148. SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Paul F. O’Reilly
  149. British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    • Sandosh Padmanabhan
  150. Department of Medicine, Columbia University Medical Center, New York, NY, USA

    • Walter Palmas
  151. Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Aarno Palotie
  152. The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Aarno Palotie
  153. University of Tartu, Tartu, Estonia

    • Markus Perola
  154. German Center for Cardiovascular Disease Research (DZHK), partner site Munich, Neuherberg, Germany

    • Annette Peters
  155. Psychiatric Hospital “Sveti Ivan”, Zagreb, Croatia

    • Ozren Polasek
  156. Department of Neurology, General Central Hospital, Bolzano, Italy

    • Peter P. Pramstaller
  157. Department of Neurology, University of Lübeck, Lübeck, Germany

    • Peter P. Pramstaller
  158. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

    • Olli T. Raitakari
  159. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

    • Olli T. Raitakari
  160. Fujian Key Laboratory of Geriatrics, Department of Geriatric Medicine, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China

    • Meixia Ren
  161. Institute of Physiology, University Medicine Greifswald, Karlsburg, Germany

    • Rainer Rettig
  162. Department of Biostatistics, University of Washington, Seattle, WA, USA

    • Kenneth Rice
  163. Harvard Medical School, Boston, MA, USA

    • Paul M. Ridker
    •  & Daniel I. Chasman
  164. Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    • Samuli Ripatti
  165. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK

    • Igor Rudan
  166. Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

    • Yasaman Saba
    •  & Helena Schmidt
  167. The New York Academy of Medicine, New York, NY, USA

    • David Siscovick
  168. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK

    • John M. Starr
  169. Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK

    • David J. Stott
  170. Population Health Research Institute, St George’s, University of London, London, UK

    • David P. Strachan
  171. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Morris A. Swertz
  172. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    • Alexander Teumer
  173. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

    • Stella Trompet
  174. Dasman Diabetes Institute, Dasman, Kuwait

    • Jaakko Tuomilehto
  175. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

    • Jaakko Tuomilehto
  176. Department of Public Health, University of Helsinki, Helsinki, Finland

    • Jaakko Tuomilehto
  177. Saudi Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

    • Jaakko Tuomilehto
  178. Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands

    • André G. Uitterlinden
  179. Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

    • Ahmad Vaez
  180. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

    • Uwe Völker
  181. Department of Internal Medicine, University Hospital, CHUV, Lausanne, Switzerland

    • Peter Vollenweider
  182. Experimental Genetics Division, Sidra Medical and Research Center, Doha, Qatar

    • Dragana Vuckovic
  183. Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK

    • Sarah H. Wild
  184. Department of Biology, Faculty of Medicine, University of Split, Split, Croatia

    • Tatijana Zemunik
  185. The National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK

    • Adam S. Butterworth
    •  & John Danesh
  186. Division of Cardiology, University Hospital, Basel, Switzerland

    • David Conen
  187. Division of Cardiology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

    • David Conen
  188. Institute of Genetic and Biomedical Research, National Research Council (CNR), Monserrato, Cagliari, Italy

    • Francesco Cucca
  189. Department of Biomedical Sciences, University of Sassari, Sassari, Italy

    • Francesco Cucca
  190. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

    • Markku Laakso
  191. Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    • Edward G. Lakatta
  192. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands

    • Dennis O. Mook-Kanamori
  193. Labormedizinisches Zentrum Dr. Risch, Schaan, Liechtenstein

    • Lorenz Risch
  194. Private University of the Principality of Liechtenstein, Triesen, Liechtenstein

    • Lorenz Risch
  195. University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    • Lorenz Risch
  196. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    • Pim van der Harst
  197. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Christopher Newton-Cheh
  198. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    • Christopher Newton-Cheh
  199. Tennessee Valley Healthcare System (Nashville VA) & Vanderbilt University, Nashville, TN, USA

    • Adriana M. Hung
  200. VA Boston Healthcare, Section of Cardiology and Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Christopher J. O’Donnell
  201. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA

    • Bruce M. Psaty
  202. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    • Bruce M. Psaty
  203. National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust and Imperial College London, London, UK

    • Paul Elliott
  204. UK Dementia Research Institute (UK DRI) at Imperial College London, London, UK

    • Paul Elliott
  205. Health Data Research–UK London substantive site, London, UK

    • Paul Elliott

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Consortia

  1. the Million Veteran Program

    Contributions

    Central analysis. E.E., H.R.W., D.M.-A., B.M., R.P., H.G., G.N., N.D., C.P.C., I. Karaman, F.L.N., M.E., K.W., E.T., L.V.W.

    Writing of the manuscript. E.E., H.R.W., D.M.-A., B.M., R.P., H.G., I.T., M.R.B., L.V.W., P.E., M.J.C. (with group leads E.E., H.R.W., L.V.W., P.E., M.J.C.). All authors critically reviewed and approved the final version of the manuscript.

    ICBP-Discovery contributor. (3C-Dijon) S.D., M.S., P. Amouyel, G.C., C.T.; (AGES-Reykjavik) V. Gudnason, L.J.L., A.V.S., T.B.H.; (ARIC) D.E.A., E.B., A. Chakravarti, A.C.M., P.N.; (ASCOT) N.R.P., D.C.S., A.S., S. Thom, P.B.M., P. Sever, M.J.C., H.R.W.; (ASPS) E.H., Y.S., R. Schmidt, H. Schmidt; (B58C) D.P.S., (BHS) A. James, N. Shrine; (BioMe (formerly IPM)) E.P.B., Y. Lu, R.J.F.L.; (BRIGHT) J.C., M.F., M.J.B., P.B.M., M.J.C., H.R.W.; (CHS) J.C.B., K.R., K.D.T., B.M.P.; (Cilento study) M. Ciullo, T. Nutile, D.R., R. Sorice; (COLAUS) M. Bochud, Z.K., P.V.; (CROATIA_Korcula) J. Marten, A.F.W.; (CROATIA_SPLIT) I. Kolcic, O.P., T.Z.; (CROATIA_Vis) J.E.H., I.R., V.V.; (EPIC) K.-T.K., R.J.F.L., N.J.W.; (EPIC-CVD) W.-Y.L., P. Surendran, A.S.B., J. Danesh, J.M.M.H.; (EPIC-Norfolk, Fenland-OMICS, Fenland-GWAS) J.-H.Z.; (EPIC-Norfolk, Fenland-OMICS, Fenland-GWAS, InterAct-GWAS) J.L., C.L., R.A.S., N.J.W.; (ERF) N.A., B.A.O., C.M.v.D.; (Fenland-Exome, EPIC-Norfolk-Exome) S.M.W., FHS, S.-J.H., D.L.; (FINRISK (COROGENE_CTRL)) P.J., K.K., M.P., A.-P.S.; (FINRISK_PREDICT_CVD) A.S.H., A. Palotie, S.R., V.S.; (FUSION) A.U.J., M. Boehnke, F. Collins, J.T., (GAPP) S. Thériault, G.P., D.C., L.R.; (Generation Scotland (GS:SFHS)) T. Boutin, C.H., A. Campbell, S.P.; (GoDARTs) N. Shah, A.S.F.D., A.D.M., C.N.A.P.; (GRAPHIC) P.S.B., C.P.N., N.J.S., M.D.T.; (H2000_CTRL) A. Jula, P.K., S. Koskinen, T. Niiranen; (HABC) Y. Liu, M.A.N., T.B.H.; (HCS) J.R.A., E.G.H., C.O., R.J. Scott; (HTO) K.L.A., H.J.C., B.D.K., M. Tomaszewski, C. Mamasoula; (ICBP-SC) G.A., T.F., M.-R.J., A.D.J., M. Larson, C.N.-C.; (INGI-CARL) I.G., G.G., A. Morgan, A.R.; (INGI-FVG) M. Brumat, M. Cocca, P.G., D.V.; (INGI-VB) C.M.B., C.F.S., D.T., M. Traglia; (JUPITER) F.G., L.M.R., P.M.R., D.I.C.; (KORA S3) C.G., M. Laan, E.O., S.S.; (KORA S4) A. Peters, J.S.R.; (LBC1921) S.E.H., D.C.M.L., A. Pattie, J.M.S.; (LBC1936) G.D., I.J.D., A.J.G., L.M.L.; (Lifelines) N.V., M.H.d.B., M.A.S., P.v.d.H.; (LOLIPOP) J.C.C., J.S.K., B.L., W.Z.; (MDC) P. Almgren, O.M.; (MESA) X.G., W.P., J.I.R., J.Y.; (METSIM) A.U.J., M. Laakso; (MICROS) F.D.G.M., A.A.H., P.P.P.; (MIGEN) R.E., S. Kathiresan, J. Marrugat, D.S.; (ΝΕΟ) R.L.-G., R.d.M., R.N., D.O.M.-K.; (NESDA) Y.M., I.M.N., B.W.J.H.P., H. Snieder; (NSPHS) S.E., U.G., Å. Johansson; (NTR) D.I.B., E.J.d.G., J.-J.H., G.W.; (ORCADES) H.C., P.K.J., S.H.W., J.F.W.; (PIVUS) L. Lin, C.M.L., J.S., A. Mahajan; (Prevend) N.V., P.v.d.H.; (PROCARDIS) M.F., A. Goel, H.W.; (PROSPER) J. Deelen, J.W.J., D.J.S., S. Trompet; (RS) O.H.F., A. Hofman, A.G.U., G.C.V.; (SardiNIA) J. Ding, Y.Q., F. Cucca, E.G.L.; (SHIP) M.D., R.R., A.T., U.V.; (STR) M. Frånberg, A. Hamsten, R.J. Strawbridge, E.I.; (TRAILS) C.A.H., A.J.O., H.R., P.J.v.d.M.; (TwinsUK) M.M., C. Menni, T.D.S.; (UKHLS) B.P.P., E.Z.; (ULSAM) V. Giedraitis, A.P.M., A. Mahajan, E.I.; (WGHS) F.G., L.M.R., P.M.R., D.I.C.; (YFS) M.K., T.L., L.-P.L., O.T.R.

    ICBP analysis. T. Blake, C.Y.D., G.B.E, J.K., L. Lin, P.F.O., P.J.M., Q.T.N., R. Jansen, R. Joehanes, A.M.E., A.V.

    Replication study contributor. (MVP) J.N.H., A. Giri, D.R.V.E., Y.V.S., K.C., J.M.G., P.W.F.W., P.S.T., C.P.K., A.M.H., C.J.O., T.L.E.; (EGCUT) T.E., R.M., L.M., A. Metspalu.

    Airwave Health Monitoring Study. E.E., H.G., A.-C.V., R.P., I. Karaman, I.T., P.E.

    Competing interests

    K.W. is a commercial partnerships manager for Genomics England, a UK Government company. M.A.N. consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare, among others. A.S.B. has received grants outside of this work from Merck, Pfizer, Novartis, AstraZeneca, Biogen and Bioverativ and personal fees from Novartis. J. Danesh has the following competing interests: Pfizer Population Research Advisory Panel (grant), AstraZeneca (grant), Wellcome Trust (grant), UK Medical Research Council (grant), Pfizer (grant), Novartis (grant), NHS Blood and Transplant (grant), UK Medical Research Council (grant), British Heart Foundation (grant), UK National Institute of Health Research (grant), European Commission (grant), Merck Sharp and Dohme UK Atherosclerosis (personal fees), Novartis Cardiovascular and Metabolic Advisory Board (personal fees), British Heart Foundation (grant), European Research Council (grant), Merck (grant). B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. M.J.C. is Chief Scientist for Genomics England, a UK Government company.

    Corresponding authors

    Correspondence to Paul Elliott or Mark J. Caulfield.

    Integrated supplementary information

    1. Supplementary Figure 1 GWAS discovery Manhattan plots.

      (a-c) Manhattan plots for systolic blood pressure (SBP) (a), diastolic blood pressure (DBP) (b), and pulse pressure (PP) (c). P-value results from the GWAS discovery meta-analysis (n = 757,601), were derived using inverse variance fixed effects meta-analysis and they are plotted on a –log10 scale for all SNPs with minor allele frequency (MAF) ≥ 1%. SNPs within the 274 known loci (± 500 kb; linkage disequilibrium r2 ≥ 0.1) are highlighted in green.

    2. Supplementary Figure 2 Effect sizes of all blood pressure–associated loci.

      (a) Plot shows strong correlation between the published effect size estimates (x-axis) from literature vs. the effect sizes from our discovery meta-analysis (y-axis), for known SNPs, color-coded according to the published primary trait from the first published report. From the 357 validated SNPs listed in Supplementary Table 4 from the 274 published loci, 327 are available within the MAF ≥ 1% HRC-imputed data. For comparison of effect sizes, we only consider 299 such SNPs that have been identified from main-effect genetic association studies within Europeans (that is excluding any SNPs from interaction/stratified/multi-phenotype analysis, or from studies of other ancestries). For reliable comparison of effect sizes, we further restrict to the 284 known SNPs that reach genome-wide significance within the discovery meta-analysis for at least one blood pressure trait. The r2 value is presented to show the correlation between published and observed effect sizes. (b-d) Trait-specific plots for SBP (b), DBP (c) and PP (d) (SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure). Across all plots, the 284 “known” SNPs (black squares) from a are compared against the 325 novel sentinel SNPs from the 2-stage analysis (red circles), the 210 novel sentinel SNPs from the 1-stage analysis (green triangles), and the 92 SNPs (blue diamonds) replicated for the first time from Hoffman et al.9. Each SNP is only plotted in one of the trait-specific plots, according to the published primary trait for the known SNPs, or the primary trait for the novel/replicated SNPs. For all SNPs, we show the relationship between MAF on the x-axis and the effect size (mmHg) on the y-axis, where results are taken from the UKB+ICBP discovery meta-analysis. All meta-analysis results were computed using inverse variance fixed effects models. The different symbols and colors distinguish the “known” vs “novel-2stage” vs “novel-1stage” vs “replicated-Hoffman” SNPs, and show that, in general, the novel SNPs have smaller effect sizes than known SNPs, and that there is no significant difference (P = 0.447) between the effect sizes of the 1-stage (n = 757,601) and 2-stage (n = 1,006,863) novel SNPs. (UKB, UK Biobank; ICBP, International Consortium of Blood Pressure).

    3. Supplementary Figure 3 Venn diagram of novel locus results.

      For all 535 novel loci, we show the blood pressure traits associated with each locus. We present the 2-stage loci first, followed by the 1-stage loci. The locus names provided in alphabetical order correspond to the nearest annotated gene. SNPs, single nucleotide polymorphisms; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; UKB, UK Biobank; ICBP, International Consortium of Blood Pressure.

    4. Supplementary Figure 4 Overview of functional annotation and prioritization of genome-wide associated variants and genes.

      SNPs, single nucleotide polymorphisms; LD, linkage disequilibrium; eQTL, expression quantitative trait loci; UCSC, University of California Santa Cruz (UCSC) genome browser; IPA, Ingenuity Pathway Analysis (IPA) software (IPA®,QIAGEN Redwood City,www.qiagen.com/ingenuity); DEPICT, Data-driven Expression Prioritized Integration for Complex Traits; GREAT, Genomic Regions Enrichment of Annotations Tool.

    5. Supplementary Figure 5 DEPICT enrichment analysis.

      DEPICT software was used to investigate enrichment of a range of biological properties. In each case, we compared known sentinel SNPs (n = 357) to all known and novel SNPs with P < 1 x 10−12 (n = 227). The gene set enrichment analysis algorithm is described in Pers et al.66. Enrichment –log P-value is reported for both groups; we also present delta –log P-value as a measure of novelty introduced by novel associations reported. Enrichment categories are as follows. (a) Enrichment of tissues and cell types. (b) GO annotation. (c) Protein-protein interaction subnetwork annotation. (d) Mammalian phenotype annotation.

    6. Supplementary Figure 6 Enrichments of eQTLs.

      535 novel blood pressure associated SNPs and the SNPs in LD r2 > 0.8 were annotated for their effect on gene expression using the GTEx portal. The number of eGenes associated with blood pressure SNPs in a given tissue/cell type was normalized with the total number of eGenes in that tissue, and Z-score was calculated using the trimmed mean and standard deviation of the normalized scores. Tissues of the same tissue group were colored the same.

    7. Supplementary Figure 7 FORGE DNase I–sensitive region enrichment in known sentinel SNPs, compared to known and novel sentinel SNP associations for blood pressure.

      Sentinel SNPs were investigated for enrichment in ENCODE DNase I regulatory regions using FORGE. The background probability of overlap is determined from the 1,000 background set overlap counts and the probability of the observed test result under a binomial distribution is calculated. The P-value thresholds of 0.05 and 0.01 are corrected for multiple testing by division by the number of tissue groupings tested, and the corrected threshold is used. Strongest enrichment in known SNPs was seen in vasculature (Human Aortic artery fibroblast (AoAF) and also Human Villous Mesenchymal Fibroblasts (HVMF) found in placenta). Enrichment in all known and novel SNPs was increased across vasculature (AoAF; HMVEC, Human microvascular endothelial cells) and highly vascularized tissues. Tissues in red are significant after correction for false discovery.

    8. Supplementary Figure 8 Ingenuity pathway analysis of blood pressure genes.

      Ingenuity pathway analysis for genes mapped to 357 sentinel SNPs at 274 known loci and genes mapped to all 901 loci. Sentinel gene mapping is compared to genes identified by extended LD (r2 > 0.8). Pathway enrichment is represented as –log P-value. (a) Canonical pathway enrichment. (b) Upstream regulator enrichment. (c) Disease and Biofunction enrichment.

    9. Supplementary Figure 9 Exploring known and novel drug mechanisms in blood pressure.

      The figure summarizes known and novel target opportunities highlighted by blood pressure genetics. Ingenuity pathway analysis was used to create a network of 6,562 genes showing direct interaction with 145 known blood pressure target genes. This network was compared with all genes that are either directly associated with blood pressure or linked by LD (r2 > 0.8). Overlap between genetic associated genes and the BP drug interactome demonstrates genetic support for known drug mechanisms. Drugged or druggable genes showing genetic association with blood pressure, but no interaction with the known BP drug interactome, represent potentially new mechanisms in blood pressure drug development and repositioning. Number of known and novel drugged/druggable gene associations are shown in parentheses.

    10. Supplementary Figure 10 Comparison of β effect sizes between individuals of European (n = 757,601), African (n = 7,782) and South Asian (n = 10,323) ancestry.

      (a-f) Scatterplots showing the direction of the standardized regression coefficient (beta) of novel (red) and known (grey) blood pressure variants between Europeans and Africans (a-c) and South Asians (d-f), on the three studied blood pressure phenotypes.

    11. Supplementary Figure 11 Correlation and distribution of minor allele frequencies of blood pressure variants in individuals of European (n = 757,601), African (n = 7,782) and South Asian (n = 10,323) ancestry.

      (a,b) Scatterplots showing the correlation and the distribution of MAF of novel (red) and known (grey) blood pressure variants between Europeans and Africans (a) and Europeans and South Asians (b). ρ is the Pearson correlation coefficient.

    12. Supplementary Figure 12 Ethnicity clustering performed using PCA.

      PC1 is plotted against PC2 for all n = 486,683 UK Biobank participants post-QC, color-coded according to the five ethnic clusters created from our K-means PCA clustering, from which only “White” Caucasians are selected for analysis of individuals of European ancestry. (a) Plot showing the clustering for all subjects. (b) Plots showing the subsets of individuals selected for race-stratified analysis, after combining information together from both the PCA clustering and the self-reported ethnicity. PCA, principal component analysis; QC, quality control; PCs, principal components.

    13. Supplementary Figure 13 Quantile–quantile plots.

      (a-c) QQ plots of results for systolic blood pressure (SBP) (a), diastolic blood pressure (DBP) (b), and pulse pressure (PP) (c) from GWAS discovery (n = 757,601). The black curves are based on all SNPs in the corresponding analysis, with MAF ≥ 1%. The green curves are results after excluding SNPs within the 274 known loci (± 500 kb; linkage disequilibrium r2 ≥ 0.1). The P-values have been derived from inverse variance fixed effects meta-analysis.

    Supplementary information

    1. Supplementary Text and Figures

      Supplementary Figures 1–13, Supplementary Table Legends and Supplementary Notes 1 and 2

    2. Reporting Summary

    3. Supplementary Tables 1–25

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    DOI

    https://doi.org/10.1038/s41588-018-0205-x

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