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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Nature Genetics volume 48, pages 1151–1161 (2016)Cite this article

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Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure– or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

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Figure 1: Study design and workflow diagram for single-variant discovery analyses.
Figure 2: Overlap of the 30 new blood pressure–associated loci across SBP, DBP, PP and HTN.
Figure 3: Study design for conditional analyses and rare variant gene-based discovery analyses.
Figure 4: Locus plot for A2ML1 and secondary amino acid structure of the gene product.

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Acknowledgements

Full acknowledgments appear in the Supplementary Note.

Author information

Author notes

  1. Anton J M de Craen and John Danesh: Deceased

  2. Praveen Surendran, Fotios Drenos, Robin Young, Helen Warren, James P Cook, Alisa K Manning, Niels Grarup, Xueling Sim, Folkert W Asselbergs, Cecilia M Lindgren, John Danesh, Louise V Wain, Adam S Butterworth, Joanna M M Howson and Patricia B Munroe: These authors contributed equally to this work

  3. Danish Saleheen, Joanna M M Howson and Patricia B Munroe: These authors jointly directed this work.

  4. These authors contributed equally to this work

  5. These authors jointly supervised directed this work.

Authors and Affiliations

  1. Department of Public Health and Primary Care, MRC/BHF Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, UK

    Praveen Surendran, Robin Young, Daniel R Barnes, James R Staley, Daniel F Freitag, Stephen Burgess, Emanuele Di Angelantonio, Rajiv Chowdhury, Danish Saleheen, John Danesh, Adam S Butterworth & Joanna M M Howson

  2. Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK

    Fotios Drenos

  3. Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK

    Fotios Drenos

  4. Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK

    Helen Warren, Kate Witkowska, Susan Shaw-Hawkins, Morris J Brown, Mark J Caulfield & Patricia B Munroe

  5. National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK

    Helen Warren, Kate Witkowska, Andrew Tinker, Mark J Caulfield & Patricia B Munroe

  6. Department of Health Sciences, University of Leicester, Leicester, UK

    James P Cook, Martin D Tobin & Louise V Wain

  7. Department of Biostatistics, University of Liverpool, Liverpool, UK

    James P Cook & Andrew P Morris

  8. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Alisa K Manning, Taru Tukiainen & Tõnu Esko

  9. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA

    Alisa K Manning, Taru Tukiainen, Niek Verweij, Tõnu Esko, Aarno Palotie, Sekar Kathiresan, Christopher Newton-Cheh & Cecilia M Lindgren

  10. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA

    Alisa K Manning

  11. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Niels Grarup, Jette Bork-Jensen, Anette P Gjesing, Torben Hansen & Oluf Pedersen

  12. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Xueling Sim, Anne U Jackson, Jeroen R Huyghe, Michael Boehnke & Heather M Stringham

  13. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA

    Xueling Sim, Anne U Jackson, Jeroen R Huyghe, Michael Boehnke & Heather M Stringham

  14. Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore

    Xueling Sim

  15. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands

    Vinicius Tragante, Magdalena Harakalova & Folkert W Asselbergs

  16. Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

    Taru Tukiainen & Aarno Palotie

  17. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

    Hanieh Yaghootkar

  18. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    Nicholas Masca, Christopher P Nelson, Maciej Tomaszewski & Nilesh J Samani

  19. National Institute for Health Research Leicester Biomedical Research Unit in Cardiovascular Disease, Leicester, UK

    Nicholas Masca, Christopher P Nelson, Maciej Tomaszewski & Nilesh J Samani

  20. Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Teresa Ferreira, Lorraine Southam, N William Rayner, Neil R Robertson, Mark I McCarthy, Anubha Mahajan, Andrew P Morris & Cecilia M Lindgren

  21. Heart Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Olga Giannakopoulou, Andrew Tinker, Kathleen E Stirrups, Eirini Marouli & Panos Deloukas

  22. Estonian Genome Center, University of Tartu, Tartu, Estonia

    Evelin Mihailov, Markus Perola, Tõnu Esko, Reedik Mägi & Andres Metspalu

  23. National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA

    Chunyu Liu, Jennifer E Huffman, Ramachandran S Vasan & Honghuang Lin

  24. Division of Statistical Genomics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA

    Aldi T Kraja

  25. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

    Aldi T Kraja

  26. Department of Clinical Biochemistry Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark

    Sune Fallgaard Nielsen & Børge Grønne Nordestgaard

  27. Centre for Non-Communicable Diseases, Karachi, Pakistan

    Asif Rasheed, Maria Samuel, Philippe Frossard & Danish Saleheen

  28. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Wei Zhao & Danish Saleheen

  29. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA

    Lori L Bonnycastle, Narisu Narisu, Amy J Swift & Francis S Collins

  30. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK

    Lorraine Southam, Angela Matchan, N William Rayner, Samuli Ripatti & Eleftheria Zeggini

  31. Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    Jonathan Marten, Jennifer E Huffman & Caroline Hayward

  32. Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

    Alena Stančáková, Johanna Kuusisto & Markku Laakso

  33. Department of Clinical Sciences, University of Lund, Malmö, Sweden

    Cristiano Fava, Therese Ohlsson & Olle Melander

  34. Department of Medicine, University of Verona, Verona, Italy

    Cristiano Fava

  35. Department of Haematology, University of Cambridge, Cambridge, UK

    Kathleen E Stirrups & Nicole Soranzo

  36. Department of Health, National Institute for Health and Welfare, Helsinki, Finland

    Jukka Kontto, Markus Perola, Aki S Havulinna, Eero Kajantie, Jaana Lindström, Pekka Jousilahti, Satu Männistö, Jaakko Tuomilehto, Veikko Salomaa, Kari Kuulasmaa & Jarmo Virtamo

  37. Institute of Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland

    Markus Perola

  38. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA

    He Zhang & Cristen J Willer

  39. Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK

    Louise A Donnelly, John M Connell, Alex S F Doney & Colin N A Palmer

  40. Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, UK

    Christopher J Groves, N William Rayner, Matt J Neville, Neil R Robertson, Fredrik Karpe & Mark I McCarthy

  41. National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, Oxford, UK

    Matt J Neville, Fredrik Karpe & Mark I McCarthy

  42. Section of Investigative Medicine, Imperial College London, London, UK

    Andrianos M Yiorkas & Alexandra I F Blakemore

  43. Department of Life Sciences, Brunel University London, London, UK

    Andrianos M Yiorkas & Alexandra I F Blakemore

  44. Institute of Biomedicine, Biocenter Oulu, University of Oulu, Oulu, Finland

    Karl-Heinz Herzig

  45. Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland

    Karl-Heinz Herzig

  46. Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

    Eero Kajantie

  47. Department of Obstetrics and Gynaecology, Oulu University Hospital and University of Oulu, Oulu, Finland

    Eero Kajantie

  48. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

    Weihua Zhang, Evangelos Evangelou, Alireza Moayyeri, Anne-Claire Vergnaud & John C Chambers

  49. Department of Cardiology, Ealing Hospital, Middlesex, UK

    Weihua Zhang, John C Chambers & Jaspal S Kooner

  50. Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK

    Sara M Willems, Jian’an Luan, Robert A Scott, Claudia Langenberg & Nick J Wareham

  51. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden

    Lars Lannfelt

  52. Department of Neurosciences, Section of Biology and Genetics, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

    Giovanni Malerba & Elisabetta Trabetti

  53. Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK

    Nicole Soranzo

  54. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK

    Nicole Soranzo, Emanuele Di Angelantonio, John Danesh & Adam S Butterworth

  55. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Niek Verweij, Rudolf A de Boer, Peter van der Meer & Pim van der Harst

  56. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Niek Verweij, Sekar Kathiresan & Christopher Newton-Cheh

  57. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece

    Evangelos Evangelou

  58. Farr Institute of Health Informatics Research, Institute of Health Informatics, University College London, London, UK

    Alireza Moayyeri

  59. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden

    Alaitz Poveda, Tibor V Varga, Frida Renström & Paul W Franks

  60. Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain

    Alaitz Poveda

  61. Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Muriel Caslake, Ian Ford & Chris J Packard

  62. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands

    Anton J M de Craen & Stella Trompet

  63. Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

    Stella Trompet & J Wouter Jukema

  64. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    Sarah E Harris, David C M Liewald, Riccardo Marioni, Ian J Deary & John M Starr

  65. Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    Sarah E Harris, Riccardo Marioni & David J Porteous

  66. Department of Psychology, University of Edinburgh, Edinburgh, UK

    David C M Liewald & Ian J Deary

  67. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    Riccardo Marioni

  68. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK

    Cristina Menni & Timothy D Spector

  69. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece

    Aliki-Eleni Farmaki & George Dedoussis

  70. Department of Biobank Research, Umeå University, Umeå, Sweden

    Göran Hallmans & Frida Renström

  71. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

    Maija Hassinen, Pirjo Komulainen, Timo A Lakka & Rainer Rauramaa

  72. Department of Medicine, Section of Cardiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA

    Ramachandran S Vasan

  73. Department of Medicine, Sections of Preventive Medicine and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA

    Ramachandran S Vasan

  74. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    Janine F Felix

  75. Development Management and Planning, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA

    Maria Uria-Nickelsen

  76. Pfizer Worldwide Research and Development, Stockholm, Sweden

    Anders Malarstig

  77. Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA

    Dermot F Reilly

  78. Merck Research Laboratories, Cardiometabolic Disease, Kenilworth, New Jersey, USA

    Maarten Hoek & Thomas F Vogt

  79. CHDI Management/CHDI Foundation, Princeton, New Jersey, USA

    Thomas F Vogt

  80. Department of Medicine, Section of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, USA

    Honghuang Lin

  81. Institute of Epidemiology and Biobank Popgen, Kiel University, Kiel, Germany

    Wolfgang Lieb

  82. Neurology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK

    Matthew Traylor & Hugh S Markus

  83. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Heather M Highland & Anne E Justice

  84. Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

    Matti Uusitupa

  85. Research Unit, Kuopio University Hospital, Kuopio, Finland

    Matti Uusitupa

  86. Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Kuopio, Finland

    Timo A Lakka

  87. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland

    Timo A Lakka & Rainer Rauramaa

  88. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    Ozren Polasek & Igor Rudan

  89. Faculty of Medicine, University of Split, Split, Croatia

    Ozren Polasek

  90. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

    Olov Rolandsson & Paul W Franks

  91. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA

    Paul W Franks

  92. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK

    John M Starr

  93. Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Anna F Dominiczak, Naveed Sattar & Sandosh Padmanabhan

  94. Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands

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  95. Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA

    Tõnu Esko

  96. Institute of Molecular and Cell Biology, Tartu, Estonia

    Andres Metspalu

  97. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

    Pim van der Harst

  98. Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands

    Pim van der Harst & Folkert W Asselbergs

  99. Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy

    Giovanni Gambaro

  100. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    Erik Ingelsson & Lars Lind

  101. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA

    Erik Ingelsson

  102. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands

    Paul I W de Bakker

  103. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands

    Paul I W de Bakker & Mattijs E Numans

  104. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands

    Mattijs E Numans

  105. Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark

    Ivan Brandslund

  106. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark

    Ivan Brandslund

  107. Medical Department, Lillebaelt Hospital, Vejle, Denmark

    Cramer Christensen

  108. Department of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Vejle, Denmark

    Eva R B Petersen

  109. Department of Internal Medicine, South Ostrobothnia Central Hospital, Seinäjoki, Finland

    Eeva Korpi-Hyövälti

  110. Department of Internal Medicine, Tampere University Hospital, Tampere, Finland

    Heikki Oksa

  111. Imperial College Healthcare NHS Trust, London, UK

    John C Chambers & Jaspal S Kooner

  112. National Heart and Lung Institute, Imperial College London, London, UK

    Jaspal S Kooner & Peter Sever

  113. Institute of Reproductive and Developmental Biology, Imperial College London, London, UK

    Steve Franks

  114. Department of Epidemiology and Biostatistics, Medical Research Council Public Health England Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St. Mary′s Campus, London, UK

    Marjo-Riitta Jarvelin & Paul Elliott

  115. Centre for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

    Marjo-Riitta Jarvelin

  116. Biocenter Oulu, University of Oulu, Oulu, Finland

    Marjo-Riitta Jarvelin

  117. Unit of Primary Care, Oulu University Hospital, Oulu, Finland

    Marjo-Riitta Jarvelin

  118. Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark

    Lise L Husemoen, Allan Linneberg, Tea Skaaby & Betina Thuesen

  119. Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark

    Allan Linneberg

  120. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Allan Linneberg

  121. Dasman Diabetes Institute, Dasman, Kuwait

    Jaakko Tuomilehto

  122. Centre for Vascular Prevention, Danube University Krems, Krems, Austria

    Jaakko Tuomilehto

  123. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

    Jaakko Tuomilehto

  124. School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, UK

    Andrew D Morris

  125. Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway

    Oddgeir Lingaas Holmen & Kristian Hveem

  126. St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway

    Oddgeir Lingaas Holmen

  127. Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway

    Kristian Hveem

  128. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA

    Cristen J Willer

  129. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Cristen J Willer

  130. Folkhälsan Research Centre, Helsinki, Finland

    Tiinamaija Tuomi

  131. Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland

    Tiinamaija Tuomi

  132. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    Tiinamaija Tuomi, Leif Groop, Aarno Palotie & Samuli Ripatti

  133. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden

    Leif Groop

  134. Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland

    AnneMari Käräjämäki

  135. Diabetes Center, Vaasa Health Care Center, Vaasa, Finland

    AnneMari Käräjämäki

  136. Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

    Aarno Palotie

  137. Department of Public Health, University of Helsinki, Helsinki, Finland

    Samuli Ripatti

  138. ICDDR, B, Mohakhali, Dhaka, Bangladesh

    Dewan S Alam

  139. National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh

    Abdulla al Shafi Majumder

  140. School of Public Health, Imperial College London, London, UK

    Neil Poulter

  141. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

    Alice V Stanton

  142. University of Lille, UMR 1167, Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France

    Philippe Amouyel

  143. INSERM, Lille, France

    Philippe Amouyel

  144. CHU Lille, Public Health, Lille, France

    Philippe Amouyel

  145. Institut Pasteur de Lille, Lille, France

    Philippe Amouyel

  146. Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France

    Dominique Arveiler

  147. Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany

    Stefan Blankenberg

  148. University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Stefan Blankenberg

  149. Department of Epidemiology, UMR 1027, INSERM, Toulouse University, CHU Toulouse, Toulouse, France

    Jean Ferrières

  150. UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK

    Frank Kee

  151. Institute of Genetic Epidemiology, Helmholtz Zentrum München -German Research Center for Environmental Health, Neuherberg, Germany

    Martina Müller-Nurasyid

  152. Department of Medicine I, University Hospital Grosshadern, Ludwig Maximilians Universität, Munich, Germany

    Martina Müller-Nurasyid

  153. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

    Martina Müller-Nurasyid

  154. Department of Clinical and Experimental Medicine, Research Center in Epidemiology and Preventive Medicine, University of Insubria, Varese, Italy

    Giovanni Veronesi

  155. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia

    Panos Deloukas

  156. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA

    Sekar Kathiresan & Christopher Newton-Cheh

  157. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Sekar Kathiresan

  158. A collaboration between the University Medical Schools and NHS, Aberdeen, Dundee, Edinburgh and Glasgow, UK

    Generation Scotland

  159. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Karen L Mohlke

  160. Division of Cardiovascular Sciences, University of Manchester, Manchester, UK

    Maciej Tomaszewski

  161. Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK

    Folkert W Asselbergs

  162. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK

    Cecilia M Lindgren

  163. Wellcome Trust Sanger Institute, Hinxton, UK

    John Danesh

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Consortia

CHARGE-Heart Failure Consortium

EchoGen Consortium

METASTROKE Consortium

GIANT Consortium

EPIC-InterAct Consortium

Lifelines Cohort Study

Wellcome Trust Case Control Consortium

Understanding Society Scientific Group

EPIC-CVD Consortium

CHARGE+ Exome Chip Blood Pressure Consortium

T2D-GENES Consortium

GoT2DGenes Consortium

ExomeBP Consortium

CHD Exome+ Consortium

Contributions

Supervision and management of the project: J.M.H.H. and P.B.M. The following authors contributed to the drafting of the manuscript: J.M.M.H., P.B.M. P. Surendran, H.W., A.S.B., F.D., J.P.C., D.R.B., K.W., M. Tomaszewski, F.W.A., L.V.W., N.J.S., J.D., A.K.M., H.Y., C.M.L., N.G., X.S., T. Tukiainen, D.F.F., O.G., T.F. and V.T. All authors critically reviewed and approved the final version of the manuscript. Statistical analysis review: J.M.M.H., P. Surendran, F.D., H.W., J.P.C., R.Y., N.M., P.B.M., L.V.W., H.Y., T.F., E. Mihailov, A.D.M., A. Mahajan, A. Moayyeri, E.E., A.S.B., F.W.A., M.J.C., C.F., T.F., S.E.H., A.S.H., J.E.H., J.L., G.M., J.M., N.M., A.P.M., A. Poveda, N.J.S., R.A.S., L.S., K.E.S., M. Tomaszewski, V.T., T.V.V., N.V., K.W., A.M.Y., W. Zhang, N.G., C.M.L., A.K.M., X.S. and T. Tuomi. Central data quality control: J.M.M.H., A.S.B., P. Surendran, R.Y., F.D., H.W., J.P.C., T.F., L.V.W., P.B.M., E. Mihailov, N.M., C.M.L., N.G., X.S. and A.K.M. Central data analysis: J.M.M.H., P. Surendran, F.D., H.W., J.P.C., N.G., C.M.L., A.K.M. and X.S. Pathway analysis and literature review: J.M.M.H., D.R.B., P.B.M., M. Tomaszewski, K.W., V.T., O.G., A.T. and F.W.A. GWAS lookups, eQTL analysis, GRS analysis, variant annotation and enrichment analyses: J.M.M.H., A.S.B., D.R.B., J.R.S., D.F.F., F.D., M. Harakalova, P.B.M., F.W.A., T. Tuomi, C.M.L., A.K.M. and S. Burgess. Study investigators in alphabetical order by consortium (CHD Exome+, ExomeBP and GoT2D): D.S.A., P.A., E.D.A., D.A., A.S.B., R.C., J.D., J.F., I.F., P.F., J.W.J., F. Kee, A.S.M., S.F.N., B.G.N., D.S., N. Sattar, J.V., F.W.A., P.I.W.d.B., M.J.B., M.J.C., J.C.C., J.M.C., I.J.D., G.D., A.F.D., P.E., T.E., P.W.F., G.G., P.v.d.H., C.H., K.H., E.I., M.-R.J., F. Karpe, S.K., J.S.K., L. Lind, M.I.M., O.M., A. Metspalu, A.D.M., A.P.M., P.B.M., M.E.N., S.P., C.N.A.P., O. Polasek, D.J.P., S.R., O.R., I.R., V.S., N.J.S., P. Sever, T.D.S., J.M.S., N.J.W., C.J.W., E.Z., M.B., I.B., F.S.C., L.G., T.H., E.K.-H., P.J., J. Kuusisto, M.L., T.A.L., A.L., K.L.M., H.O., O. Pedersen, R.R., J.T., M.U. M.U.-N., A. Malarstig, D.F.R., M. Hoek, T.F.V. Study phenotyping in alphabetical order by consortium (CHD Exome+, ExomeBP and GoT2D): P.A., D.A., S. Blankenberg, M.C., J.F., J.W.J., F. Kee, K.K., S.F.N., B.G.N., C.J.P., A.R., M.S., N. Sattar, J.V., W. Zhao, R.A.d.B., M.J.B., M.J.C., J.C.C., J.M.C., A.F.D., A.S.F.D., L.A.D., T.E., A.-E.F., G.G., G.H., P.v.d.H., A.S.H., O.L.H., M. Hassinen, E.I., M.-R.J., F. Karpe, J.S.K., L. Lind, L. Lannfelt, G.M., A. Matchan, P.v.d.M., A. Metspalu, R. Mägi, M.J.N., M.E.N., O. Polasek, N.P., F.R., V.S., N.J.S., T.D.S., A.V.S., J.M.S., M. Tomaszewski, A.-C.V., N.V., N.J.W., T. Tuomi, C.C., L.L.H., A.T.K., P.K., J.L., S.M., E.R.B.P., A.S., T.S., H.M.S., B.T. Study data quality control and analysis in alphabetical order by consortium (CHD Exome+, ExomeBP and GoT2D): A.S.B., A.J.M.d.C., K.-H.H., J.M.M.H., A.K., J. Kontto, C. Langenberg, S.F.N., B.G.N., M.M.-N., S.P., M.P., P. Surendran, S.T., G.V., S.M.W., R.Y., F.W.A., J.P.C., F.D., A.-E.F., T.F., C.H., A. Matchan, A. Mahajan, A.P.M., P.B.M., C.N.A.P., N.W.R., F.R., N.J.S., M. Tomaszewski, V.T., H.W., H.Y., N.G., A.K.M., X.S. Exome chip data quality control in alphabetical order by consortium (CHD Exome+, ExomeBP and GoT2D): A.S.B., K.-H.H., J.M.M.H., A.K., C. Langenberg, S.F.N., B.G.N., P. Surendran, R.Y., F.W.A., P.I.W.d.B., A.I.F.B., J.C.C., J.P.C., P.D., L.A.D., F.D., E.E., C.F., T.F., S.E.H., P.v.d.H., S.S.-H., K.H., J.E.H., E.K., A. Mahajan, G.M., J.M., N.M., E. Mihailov, A. Moayyeri, A.P.M., P.B.M., C.P.N., M.J.N., C.N.A.P., A. Poveda, N.W.R., N.R.R., R.A.S., N. Soranzo, L.S., K.E.S., M.D.T., V.T., T.V.V., N.V., H.W., H.Y., A.M.Y., E.Z., W. Zhang, N.G., C.M.L., A.K.M., X.S. Exome chip data analysis in alphabetical order by consortium (CHD Exome+, ExomeBP and GoT2D): J.M.M.H., P. Surendran, R.Y., F.W.A., P.I.W.d.B., A.I.F.B., R.A.d.B., M.J.C., J.C.C., J.P.C., P.D., L.A.D., P.E., E.E., C.F., T.F., P.W.F., S.F., C.J.G., S.E.H., P.v.d.H., A.S.H., C.H., O.L.H., J.E.H., E.I., M.-R.J., F. Karpe, J.S.K., D.C.M.L., L. Lind, J.L., G.M., R. Marioni, J.M., N.M., M.I.M., P.v.d.M., O.M., C.M., E. Mihailov, A. Moayyeri, A.P.M., R. Mägi, P.B.M., C.P.N., M.J.N., T.O., A. Palotie, A. Poveda, N.W.R., N.R.R., N.J.S., R.A.S., N. Soranzo, L.S., T.D.S., K.E.S., M.D.T., E.T., V.T., T.V.V., N.V., L.V.W., N.J.W., H.W., H.Y., A.M.Y., E.Z., H.Z., W. Zhang, L.L.B., A.P.G., N.G., J.R.H., A.U.J., J.B.-J., C.M.L., A.K.M., N.N., X.S., A.S., A.J.S. GRS lookups: A.E.J., E. Marouli, H.S.M., H.L., H.M.H., J.F.F., M. Traylor, R.S.V., W.L. CHARGE EXOME-BP lookups: Study design. A.T.K., C. Liu, C.N.-C. Analysis. A.T.K., C. Liu.

Corresponding authors

Correspondence to Joanna M M Howson or Patricia B Munroe.

Ethics declarations

Competing interests

N.P. has received financial support from several pharmaceutical companies that manufacture either blood pressure -lowering or lipid-lowering agents, or both, and consultancy fees. S.K. has received research grants from Merck, Bayer and Aegerion, is on the SAB of Catabasis, Regeneron Genetics Center, Merck and Celera, has equity in San Therapeutics and Catabasis, and performs consulting for Novartis, Aegerion, Bristol Myers Squibb, Sanofi, AstraZeneca and Alnylam. P. Sever has received research awards from Pfizer. A. Malarstig and M.U.-N. are full-time employees of Pfizer. D.F.R. and M. Hoek are full-time employees of Merck. M.J.C. is Chief Scientist for Genomics England, a UK government company. The authors declare no other competing financial interests.

Additional information

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

A full list of members and affiliations appears in the Supplementary Note

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Note (PDF 19318 kb)

Supplementary Tables

Supplementary Tables 1–20 (XLSX 226 kb)

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Surendran, P., Drenos, F., Young, R. et al. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet 48, 1151–1161 (2016). https://doi.org/10.1038/ng.3654

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