Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

doi:10.1038/s41588-024-01714-w

. 2024 May;56(5):778-791.

doi: 10.1038/s41588-024-01714-w. Epub 2024 Apr 30.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Jacob M Keaton^#^{1

2}, Zoha Kamali^#^{3

4}, Tian Xie^#³, Ahmad Vaez^{5

6}, Ariel Williams¹, Slavina B Goleva¹, Alireza Ani^{3

4}, Evangelos Evangelou^{7

8

9}, Jacklyn N Hellwege^{10

11

12}, Loic Yengo¹³, William J Young^{14

15}, Matthew Traylor^{14

16}, Ayush Giri^{2

17}, Zhili Zheng^{13

18}, Jian Zeng¹³, Daniel I Chasman^{19

20}, Andrew P Morris²¹, Mark J Caulfield^{14

22}, Shih-Jen Hwang^{23

24}, Jaspal S Kooner²⁵, David Conen²⁶, John R Attia²⁷, Alanna C Morrison²⁸, Ruth J F Loos^{29

30

31}, Kati Kristiansson³², Reinhold Schmidt³³, Andrew A Hicks^{34

35}, Peter P Pramstaller^{34

35}, Christopher P Nelson^{36

37}, Nilesh J Samani^{36

37}, Lorenz Risch^{38

39}, Ulf Gyllensten⁴⁰, Olle Melander^{41

42}, Harriette Riese⁴³, James F Wilson^{44

45}, Harry Campbell⁴⁴, Stephen S Rich⁴⁶, Bruce M Psaty⁴⁷, Yingchang Lu⁴⁸, Jerome I Rotter⁴⁹, Xiuqing Guo⁴⁹, Kenneth M Rice⁵⁰, Peter Vollenweider⁵¹, Johan Sundström^{52

53}, Claudia Langenberg^{54

55

56}, Martin D Tobin^{57

58}, Vilmantas Giedraitis⁵⁹, Jian'an Luan⁵⁴, Jaakko Tuomilehto^{32

60

61}, Zoltan Kutalik^{62

63}, Samuli Ripatti^{64

65}, Veikko Salomaa³², Giorgia Girotto^{66

67}, Stella Trompet^{68

69}, J Wouter Jukema^{69

70}, Pim van der Harst^{71

72}, Paul M Ridker^{19

20}, Franco Giulianini¹⁹, Veronique Vitart⁴⁵, Anuj Goel^{73

74}, Hugh Watkins^{73

74}, Sarah E Harris⁷⁵, Ian J Deary⁷⁵, Peter J van der Most³, Albertine J Oldehinkel⁷⁶, Bernard D Keavney^{77

78}, Caroline Hayward^{45

79}, Archie Campbell^{79

80}, Michael Boehnke⁸¹, Laura J Scott⁸¹, Thibaud Boutin⁴⁵, Chrysovalanto Mamasoula⁸², Marjo-Riitta Järvelin^{83

84

85}, Annette Peters^{86

87}, Christian Gieger⁸⁸, Edward G Lakatta⁸⁹, Francesco Cucca⁹⁰, Jennie Hui^{91

92}, Paul Knekt⁹³, Stefan Enroth⁹⁴, Martin H De Borst⁹⁵, Ozren Polašek^{96

97}, Maria Pina Concas⁶⁷, Eulalia Catamo⁶⁷, Massimiliano Cocca⁶⁷, Ruifang Li-Gao⁹⁸, Edith Hofer^{99

100}, Helena Schmidt¹⁰¹, Beatrice Spedicati⁶⁶, Melanie Waldenberger^{88

102}, David P Strachan¹⁰³, Maris Laan¹⁰⁴, Alexander Teumer^{105

106}, Marcus Dörr^{106

107}, Vilmundur Gudnason^{108

109}, James P Cook¹¹⁰, Daniela Ruggiero^{111

112}, Ivana Kolcic^{97

113}, Eric Boerwinkle^{28

114}, Michela Traglia¹¹⁵, Terho Lehtimäki^{116

117}, Olli T Raitakari^{118

119}, Andrew D Johnson^{23

120}, Christopher Newton-Cheh^{18

121}, Morris J Brown¹⁴, Anna F Dominiczak¹²², Peter J Sever¹²³, Neil Poulter¹²⁴, John C Chambers¹²⁵, Roberto Elosua^{126

127

128}, David Siscovick¹²⁹, Tõnu Esko¹³⁰, Andres Metspalu¹³⁰, Rona J Strawbridge^{131

132

133}, Markku Laakso^{134

135}, Anders Hamsten¹³³, Jouke-Jan Hottenga¹³⁶, Eco de Geus^{136

137}, Andrew D Morris^{138

139}, Colin N A Palmer¹⁴⁰, Ilja M Nolte³, Yuri Milaneschi¹⁴¹, Jonathan Marten⁷⁹, Alan Wright⁷⁹, Eleftheria Zeggini^{142

143}, Joanna M M Howson^{16

144}, Christopher J O'Donnell¹⁴⁵, Tim Spector¹⁴⁶, Mike A Nalls^{147

148

149}, Eleanor M Simonsick¹⁵⁰, Yongmei Liu¹⁵¹, Cornelia M van Duijn¹⁵², Adam S Butterworth^{144

153

154

155

156}, John N Danesh^{144

153

154

155

156

157}, Cristina Menni¹⁵⁸, Nicholas J Wareham⁵⁴, Kay-Tee Khaw¹⁵⁹, Yan V Sun^{160

161}, Peter W F Wilson^{162

163}, Kelly Cho^{164

165

166}, Peter M Visscher¹³, Joshua C Denny¹; Million Veteran Program; Lifelines Cohort Study; CHARGE consortium; ICBP Consortium; Daniel Levy^{23

119}, Todd L Edwards¹⁶⁷, Patricia B Munroe^{14

22}, Harold Snieder³, Helen R Warren^{168

169}

Collaborators, Affiliations

Collaborators

Cornelia M van Duijn, Adam S Butterworth, Ahmad Vaez, Alexander Teumer, Andrew D Johnson, Andrew D Morris, Annette Peters, Anuj Goel, Archie Campbell, Bernard D Keavney, Caroline Hayward, Christopher Newton-Cheh, Christopher P Nelson, Daniel I Chasman, Daniel Levy, Daniela Ruggiero, Eco de Geus, Edith Hofer, Eleftheria Zeggini, Eric Boerwinkle, Giorgia Girotto, Helen R Warren, Hugh Watkins, Ivana Kolcic, J Wouter Jukema, Jennie Hui, Joanna M M Howson, Johan Sundström, John C Chambers, John N Danesh, Lorenz Risch, Mark J Caulfield, Markku Laakso, Martin D Tobin, Martin H De Borst, Melanie Waldenberger, Nilesh J Samani, Olle Melander, Olli T Raitakari, Ozren Polašek, Patricia B Munroe, Paul M Ridker, Pim van der Harst, Roberto Elosua, Samuli Ripatti, Terho Lehtimäki, William J Young, Zoha Kamali, Zoltan Kutalik

Affiliations

¹ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
² Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴ Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
⁵ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. a.vaez@umcg.nl.
⁶ Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran. a.vaez@umcg.nl.
⁷ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁹ Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Ioannina, Greece.
¹⁰ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
¹³ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹⁴ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁵ Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
¹⁶ Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK.
¹⁷ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁸ Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁹ Division of Preventive Medicine Brigham and Women's Hospital, Boston, MA, USA.
²⁰ Harvard Medical School, Boston, MA, USA.
²¹ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
²² NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²³ Population Sciences Branch, NHLBI Framingham Heart Study, Framingham, MA, USA.
²⁴ Department of Biostatistics, Boston University, Boston, MA, USA.
²⁵ National Heart and Lung Institute, Imperial College London, London, UK.
²⁶ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
²⁷ Faculty of Health and Medicine, University of Newcastle, New Lambton Heights, Newcastle, New South Wales, Australia.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁰ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³² Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
³³ Department of Neurology/Medical University Graz, Graz, Austria.
³⁴ Institute for Biomedicine, Eurac Research, Bolzano, Italy.
³⁵ University of Lübeck, Lübeck, Germany.
³⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
³⁷ NIHR Leicester Biomedical Research Centre, Leicester, UK.
³⁸ Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
³⁹ Department of Laboratory Medicine, Dr. Risch Anstalt, Vaduz, Liechtenstein.
⁴⁰ Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
⁴¹ Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
⁴² Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
⁴³ Interdisciplinary Center Psychopathology and Emotional Regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴⁴ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.
⁴⁵ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.
⁴⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁴⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴⁸ Vanderbilt Genetic Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁵⁰ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵¹ Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁵² Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁵³ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁵⁴ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁵⁵ Computational Medicine, Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁵⁶ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
⁵⁷ Department of Health Sciences, University of Leicester, Leicester, UK.
⁵⁸ Leicester NIHR Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵⁹ Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
⁶⁰ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁶¹ Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶² Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.
⁶³ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁶⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁶⁵ Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶⁶ Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
⁶⁷ Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, Trieste, Italy.
⁶⁸ Department Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁶⁹ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁰ Netherlands Heart Institute, Utrecht, the Netherlands.
⁷¹ Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
⁷² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁷³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷⁴ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁷⁵ Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
⁷⁶ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁷⁷ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
⁷⁸ Manchester Heart Institute, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁷⁹ Centre for Genomic and Experimental Medicine, IGC, University of Edinburgh, Edinburgh, UK.
⁸⁰ Usher Institute, University of Edinburgh, Edinburgh, UK.
⁸¹ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁸² Population Health Sciences Institute, Newcastle University, Newcastle, UK.
⁸³ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁸⁴ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁸⁵ Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
⁸⁶ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁸⁷ Lehrstuhl für Epidemiologie, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Ludwig-Maximilians-Universität München, Neuherberg, Germany.
⁸⁸ Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁸⁹ Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁹⁰ Institute of Genetic and Biomedical Research, National Research Council (CNR), Monserrato, Italy.
⁹¹ Busselton Population Medical Research Institute, Perth, Western Australia, Australia.
⁹² School of Population and Global Health, The University of Western Australia, Nedlands, Western Australia, Australia.
⁹³ Population Health Unit, Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
⁹⁴ Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Uppsala University, Uppsala, Sweden.
⁹⁵ Department of Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁹⁶ University of Split School of Medicine, Split, Croatia.
⁹⁷ Algebra University College, Zagreb, Croatia.
⁹⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁹ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
¹⁰⁰ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
¹⁰¹ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
¹⁰² German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
¹⁰³ Population Health Sciences Institute St George's, University of London, London, UK.
¹⁰⁴ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
¹⁰⁵ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁶ DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
¹⁰⁷ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁸ Icelandic Heart Association, Kopavogur, Iceland.
¹⁰⁹ Faculty of Medicine, University of Iceland, Kopavogur, Iceland.
¹¹⁰ Department of Health Data Science, University of Liverpool, Liverpool, UK.
¹¹¹ IRCCS Neuromed, Pozzilli, Italy.
¹¹² Institute of Genetics and Biophysics - 'A. Buzzati-Traverso', National Research Council of Italy, Naples, Italy.
¹¹³ Department of Public Health, University of Split School of Medicine, Split, Croatia.
¹¹⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹¹⁵ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
¹¹⁶ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
¹¹⁷ Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹¹⁸ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
¹¹⁹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
¹²⁰ The Framingham Heart Study, Framingham, MA, USA.
¹²¹ Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹²² Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹²³ International Centre for Circulatory Health, Imperial College London, London, UK.
¹²⁴ School of Public Health, Imperial College London, London, UK.
¹²⁵ Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.
¹²⁶ Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
¹²⁷ CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain.
¹²⁸ Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
¹²⁹ New York Academy of Medicine, New York, NY, USA.
¹³⁰ Institute of Genomics, University of Tartu, Tartu, Estonia.
¹³¹ Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
¹³² Health Data Research UK, Glasgow, UK.
¹³³ Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³⁴ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
¹³⁵ Kuopio University Hospital, Kuopio, Finland.
¹³⁶ Department of Biological Psychology, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, the Netherlands.
¹³⁷ Amsterdam Public Health Research Institute, Amsterdam University Medical Centre, Amsterdam, the Netherlands.
¹³⁸ Data Science, University of Edinburgh, Edinburgh, UK.
¹³⁹ Health Data Research UK, London, UK.
¹⁴⁰ Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK.
¹⁴¹ Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
¹⁴² Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
¹⁴³ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany.
¹⁴⁴ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁴⁵ VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴⁶ Department of Twin Research, King's College London, London, UK.
¹⁴⁷ Center for Alzheimer's and Related Dementias, NIA/NINDS, NIH, Bethesda, MD, USA.
¹⁴⁸ Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
¹⁴⁹ DataTecnica LLC, Washington, DC, USA.
¹⁵⁰ Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁵¹ Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
¹⁵² Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, UK.
¹⁵³ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹⁵⁴ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁵⁵ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
¹⁵⁶ National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
¹⁵⁷ Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹⁵⁸ Department of Twin Research and Genetic Epidemiology, London, UK.
¹⁵⁹ Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹⁶⁰ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
¹⁶¹ VA Atlanta Healthcare System, Decatur, GA, USA.
¹⁶² Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
¹⁶³ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
¹⁶⁴ Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁶⁵ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶⁶ Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
¹⁶⁷ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. todd.l.edwards@vumc.org.
¹⁶⁸ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. h.r.warren@qmul.ac.uk.
¹⁶⁹ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. h.r.warren@qmul.ac.uk.

^# Contributed equally.

PMID: 38689001
PMCID: PMC11096100
DOI: 10.1038/s41588-024-01714-w

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Jacob M Keaton et al. Nat Genet. 2024 May.

. 2024 May;56(5):778-791.

doi: 10.1038/s41588-024-01714-w. Epub 2024 Apr 30.

Authors

Collaborators

Cornelia M van Duijn, Adam S Butterworth, Ahmad Vaez, Alexander Teumer, Andrew D Johnson, Andrew D Morris, Annette Peters, Anuj Goel, Archie Campbell, Bernard D Keavney, Caroline Hayward, Christopher Newton-Cheh, Christopher P Nelson, Daniel I Chasman, Daniel Levy, Daniela Ruggiero, Eco de Geus, Edith Hofer, Eleftheria Zeggini, Eric Boerwinkle, Giorgia Girotto, Helen R Warren, Hugh Watkins, Ivana Kolcic, J Wouter Jukema, Jennie Hui, Joanna M M Howson, Johan Sundström, John C Chambers, John N Danesh, Lorenz Risch, Mark J Caulfield, Markku Laakso, Martin D Tobin, Martin H De Borst, Melanie Waldenberger, Nilesh J Samani, Olle Melander, Olli T Raitakari, Ozren Polašek, Patricia B Munroe, Paul M Ridker, Pim van der Harst, Roberto Elosua, Samuli Ripatti, Terho Lehtimäki, William J Young, Zoha Kamali, Zoltan Kutalik

Affiliations

¹ Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
² Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴ Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran.
⁵ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. a.vaez@umcg.nl.
⁶ Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran. a.vaez@umcg.nl.
⁷ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
⁹ Department of Biomedical Research, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Ioannina, Greece.
¹⁰ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
¹³ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹⁴ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁵ Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
¹⁶ Department of Genetics, Novo Nordisk Research Centre Oxford, Oxford, UK.
¹⁷ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁸ Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁹ Division of Preventive Medicine Brigham and Women's Hospital, Boston, MA, USA.
²⁰ Harvard Medical School, Boston, MA, USA.
²¹ Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
²² NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²³ Population Sciences Branch, NHLBI Framingham Heart Study, Framingham, MA, USA.
²⁴ Department of Biostatistics, Boston University, Boston, MA, USA.
²⁵ National Heart and Lung Institute, Imperial College London, London, UK.
²⁶ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
²⁷ Faculty of Health and Medicine, University of Newcastle, New Lambton Heights, Newcastle, New South Wales, Australia.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁰ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³¹ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³² Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
³³ Department of Neurology/Medical University Graz, Graz, Austria.
³⁴ Institute for Biomedicine, Eurac Research, Bolzano, Italy.
³⁵ University of Lübeck, Lübeck, Germany.
³⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
³⁷ NIHR Leicester Biomedical Research Centre, Leicester, UK.
³⁸ Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
³⁹ Department of Laboratory Medicine, Dr. Risch Anstalt, Vaduz, Liechtenstein.
⁴⁰ Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
⁴¹ Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
⁴² Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
⁴³ Interdisciplinary Center Psychopathology and Emotional Regulation (ICPE), Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁴⁴ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.
⁴⁵ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.
⁴⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁴⁷ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁴⁸ Vanderbilt Genetic Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁹ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁵⁰ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁵¹ Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁵² Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁵³ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁵⁴ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
⁵⁵ Computational Medicine, Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁵⁶ Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.
⁵⁷ Department of Health Sciences, University of Leicester, Leicester, UK.
⁵⁸ Leicester NIHR Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
⁵⁹ Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
⁶⁰ Department of Public Health, University of Helsinki, Helsinki, Finland.
⁶¹ Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
⁶² Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.
⁶³ Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁶⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁶⁵ Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁶⁶ Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
⁶⁷ Institute for Maternal and Child Health - IRCCS, Burlo Garofolo, Trieste, Italy.
⁶⁸ Department Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
⁶⁹ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
⁷⁰ Netherlands Heart Institute, Utrecht, the Netherlands.
⁷¹ Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
⁷² Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁷³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷⁴ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
⁷⁵ Lothian Birth Cohorts Group, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
⁷⁶ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁷⁷ Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
⁷⁸ Manchester Heart Institute, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁷⁹ Centre for Genomic and Experimental Medicine, IGC, University of Edinburgh, Edinburgh, UK.
⁸⁰ Usher Institute, University of Edinburgh, Edinburgh, UK.
⁸¹ Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
⁸² Population Health Sciences Institute, Newcastle University, Newcastle, UK.
⁸³ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
⁸⁴ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁸⁵ Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
⁸⁶ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁸⁷ Lehrstuhl für Epidemiologie, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Ludwig-Maximilians-Universität München, Neuherberg, Germany.
⁸⁸ Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁸⁹ Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
⁹⁰ Institute of Genetic and Biomedical Research, National Research Council (CNR), Monserrato, Italy.
⁹¹ Busselton Population Medical Research Institute, Perth, Western Australia, Australia.
⁹² School of Population and Global Health, The University of Western Australia, Nedlands, Western Australia, Australia.
⁹³ Population Health Unit, Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
⁹⁴ Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Uppsala University, Uppsala, Sweden.
⁹⁵ Department of Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁹⁶ University of Split School of Medicine, Split, Croatia.
⁹⁷ Algebra University College, Zagreb, Croatia.
⁹⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
⁹⁹ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.
¹⁰⁰ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
¹⁰¹ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria.
¹⁰² German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
¹⁰³ Population Health Sciences Institute St George's, University of London, London, UK.
¹⁰⁴ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
¹⁰⁵ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁶ DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
¹⁰⁷ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
¹⁰⁸ Icelandic Heart Association, Kopavogur, Iceland.
¹⁰⁹ Faculty of Medicine, University of Iceland, Kopavogur, Iceland.
¹¹⁰ Department of Health Data Science, University of Liverpool, Liverpool, UK.
¹¹¹ IRCCS Neuromed, Pozzilli, Italy.
¹¹² Institute of Genetics and Biophysics - 'A. Buzzati-Traverso', National Research Council of Italy, Naples, Italy.
¹¹³ Department of Public Health, University of Split School of Medicine, Split, Croatia.
¹¹⁴ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹¹⁵ Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
¹¹⁶ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
¹¹⁷ Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
¹¹⁸ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
¹¹⁹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
¹²⁰ The Framingham Heart Study, Framingham, MA, USA.
¹²¹ Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹²² Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹²³ International Centre for Circulatory Health, Imperial College London, London, UK.
¹²⁴ School of Public Health, Imperial College London, London, UK.
¹²⁵ Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.
¹²⁶ Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
¹²⁷ CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain.
¹²⁸ Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
¹²⁹ New York Academy of Medicine, New York, NY, USA.
¹³⁰ Institute of Genomics, University of Tartu, Tartu, Estonia.
¹³¹ Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
¹³² Health Data Research UK, Glasgow, UK.
¹³³ Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
¹³⁴ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
¹³⁵ Kuopio University Hospital, Kuopio, Finland.
¹³⁶ Department of Biological Psychology, Faculty of Behavioural and Movement Sciences, Vrije Universiteit, Amsterdam, the Netherlands.
¹³⁷ Amsterdam Public Health Research Institute, Amsterdam University Medical Centre, Amsterdam, the Netherlands.
¹³⁸ Data Science, University of Edinburgh, Edinburgh, UK.
¹³⁹ Health Data Research UK, London, UK.
¹⁴⁰ Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK.
¹⁴¹ Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
¹⁴² Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
¹⁴³ Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany.
¹⁴⁴ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁴⁵ VA Boston Healthcare System, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴⁶ Department of Twin Research, King's College London, London, UK.
¹⁴⁷ Center for Alzheimer's and Related Dementias, NIA/NINDS, NIH, Bethesda, MD, USA.
¹⁴⁸ Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
¹⁴⁹ DataTecnica LLC, Washington, DC, USA.
¹⁵⁰ Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁵¹ Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
¹⁵² Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, UK.
¹⁵³ British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK.
¹⁵⁴ Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
¹⁵⁵ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
¹⁵⁶ National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
¹⁵⁷ Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
¹⁵⁸ Department of Twin Research and Genetic Epidemiology, London, UK.
¹⁵⁹ Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Cambridge, UK.
¹⁶⁰ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
¹⁶¹ VA Atlanta Healthcare System, Decatur, GA, USA.
¹⁶² Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
¹⁶³ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
¹⁶⁴ Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁶⁵ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶⁶ Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
¹⁶⁷ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. todd.l.edwards@vumc.org.
¹⁶⁸ Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. h.r.warren@qmul.ac.uk.
¹⁶⁹ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. h.r.warren@qmul.ac.uk.

^# Contributed equally.

PMID: 38689001
PMCID: PMC11096100
DOI: 10.1038/s41588-024-01714-w

Abstract

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10^-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10^-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10^-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10^-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

PubMed Disclaimer

Conflict of interest statement

The participation of M.A.N. in this project was part of a competitive contract awarded to Data Tecnica International by the National Institutes of Health to support open science research. He also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 as a data science fellow. B.M.P. serves on the steering committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.V. received an unrestricted grant from GlaxoSmithKline to build the CoLaus study (2003). V.S. has received honoraria for consulting from Novo Nordisk and Sanofi and has ongoing research collaboration with Bayer (all unrelated to this project). R.L. is a part-time consultant of Metabolon. M.J.C. is Chief Scientist for Genomics England, a UK Government company. M. Traylor and J.M.M.H. are employees and stockholders of Novo Nordisk. C.J.O. is currently employed by Novartis Institutes for Biomedical Research (unrelated to this project) and remains credentialed as a ‘without compensation’ researcher with the Veterans Administration. T.S. is co-founder of Zoe Ltd. A.S.B. reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi. J.N.D. reports grants, personal fees and non-financial support from Merck Sharp & Dohme (MSD), grants, personal fees and non-financial support from Novartis, grants from Pfizer and grants from AstraZeneca outside the submitted work. J.N.D. sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the AstraZeneca Genomics Advisory Board (2018). E.E was co-founder and has received consultation fees from Open DNA (unrelated to this project). The other authors declare no competing interests.

Figures

**Fig. 1. Manhattan plots of SBP, DBP and PP GWAS meta-analyses, illustrating 113 novel loci.**
Manhattan plots from top to bottom show novel results of SBP, DBP and PP GWAS meta-analysis, respectively, using inverse variance-weighted method. All loci are reported at genome-wide significance threshold (5 × 10⁻⁸). Annotated in red are loci reaching the more stringent P value of 5 × 10⁻⁹.

**Fig. 2. Relationship of deciles of the SBayesRC PRSs with SBP and DBP and risk of hypertension in European ancestry individuals from Lifelines cohort (n = 10,210).**
a,b, Plots show sex-adjusted SBP and DBP (a) and sex-adjusted odds ratios of hypertension (b) comparing each of the upper nine PRS deciles with the lowest decile. Dotted lines represent mean; error bars, s.e.m. in a and 95% CI in b.

**Fig. 3. Relationship of deciles of the SBayesRC PRSs with SBP and DBP and risk of hypertension in African-American ancestry individuals from All-Of-Us cohort (n = 21,843).**
a,b, Plots show sex-adjusted mean SBP and DBP (a) and sex-adjusted odds ratios of hypertension (b) comparing each of the upper nine PRS deciles with the lowest decile. Dotted lines represent mean; error bars, s.e.m. in a and 95% CI in b.

**Extended Data Fig. 1. Manhattan plots of meta-analysis full results.**
Manhattan plots of meta-analysis full results using inverse variance-weighted method, showing 1,495, 1,504, and 1,318 significant loci for systolic (SBP, top plot), diastolic (DBP, middle plot), and pulse pressure (PP, bottom plot) in total (r² < 0.05 and 1 Mb distance).

**Extended Data Fig. 2. Comparison of the newly discovered loci with the known loci in effect size distribution.**
Comparison of the newly discovered loci with the known loci in effect size distribution, plotting Minor Allele Frequency (MAF) on the x-axis, vs GWAS effect estimate size on the y-axis, from the meta-analysis for SBP (a), DBP (b), PP (c).

**Extended Data Fig. 3. Variance explained by Polygenic Risk Scores (PRSs) at different P value thresholds.**
Variance explained by clumping and threshold Polygenic Risk Scores (PRSs) at different P value thresholds of inverse variance- weighted meta-analysis results, for SBP, DBP and PP, in the independent Lifelines cohort data.

**Extended Data Fig. 4. Relationship of deciles of the SBayesRC PRS with Pulse Pressure (PP) in Lifelines.**
Relationship of deciles of the SBayesRC PRS with Pulse Pressure (PP) in Lifelines of European ancestry (n = 10,210). Plot shows sex-adjusted mean PP comparing each of the upper nine PRS deciles with the lowest decile. Dotted lines represent 95% confidence intervals.

**Extended Data Fig. 5. Area under the ROC curve of the two models for Hypertension prediction in Lifelines.**
Area under the ROC curve (AUROC) of the two models (covariates only and covariates plus SBayesRC PRS) for Hypertension prediction in Lifelines (n = 10,210) cohort of European ancestry.

**Extended Data Fig. 6. Pairwise allele frequency and effect size comparisons of 2103 GRS SNPs between our Mega-meta results and Japan Biobank.**
Pairwise allele frequency (a) and effect size (b) comparisons of 2103 GRS SNPs between our Mega-meta results and Japan Biobank (JBB) (n∼145k). Comparisons are separately made for the 113 novel SNPs (‘Novel’), 267 additional novel SNPs from conditional analysis (‘Secondary’), and 1723 known SNPs (‘Known’). Black, red and blue represent SNPs with SBP, DBP, and PP as the best associated traits, respectively. r = Pearson’s Correlation coefficient. ‘concordant’ means the proportion of SNPs showing directional concordance between European and Japanese populations. Please note that JBB effect sizes are standardized by Z-score transformation.

**Extended Data Fig. 7. Pairwise allele frequency and effect size comparisons of 2103 GRS SNPs between our Mega-meta results and a meta-analysis of African-American ancestry individuals.**
Pairwise allele frequency (a) and effect size (b) comparisons of 2103 GRS SNPs between our Mega-meta results and a meta-analysis of African-American ancestry individuals (N = 83,890). Comparisons are separately made for the 113 novel SNPs (‘Novel’), 267 additional novel SNPs from conditional analysis (‘Secondary’), and 1723 known SNPs (‘Known’). Black, red and blue represent SNPs with SBP, DBP, and PP as the best associated traits, respectively. r = Pearson’s Correlation coefficient. ‘concordant’ means the proportion of SNPs showing directional concordance between European and African-American populations.

**Extended Data Fig. 8. PRS for PP in AA.**
Relationship of deciles of the SBayesRC PRS with PP in African-American Ancestry individuals from All-Of-Us Cohort (n = 21,843). Plots show sex-adjusted mean PP comparing each of the upper nine PRS deciles with the lowest decile. Dotted lines represent 95% confidence intervals.

**Extended Data Fig. 9. Cross-trait associations for 41 Blood Pressure novel loci with other diseases/traits.**
Cross-trait associations for 41 of the 113 Blood Pressure novel loci with other disease/trait categories from lookups within GWAS Catalog and Phenoscanner. Segment size depends on the number of locus-trait category associations.

**Extended Data Fig. 10. GRSs and PRS tested for percent variance explained in Lifelines cohort.**
Two PRSs were calculated: 1) a standard ‘benchmark’ clumping and thresholding PRS, and; 2) an ‘optimized’ PRS based on SBayesRC. GRS = Genetic Risk Score; PRS = Polygenic Risk Score; SNP = Single Nucleotide Polymorphism.

See this image and copyright information in PMC

Cited by

Hypertension precision medicine: the promise and pitfalls of pharmacogenomics.
Le NN, Frater I, Lip S, Padmanabhan S. Le NN, et al. Pharmacogenomics. 2025 Apr-Apr;26(5-6):183-206. doi: 10.1080/14622416.2025.2504865. Epub 2025 May 27. Pharmacogenomics. 2025. PMID: 40421951 Review.
Angiotensin-converting enzyme inhibitors for aortic stenosis: a drug-target Mendelian randomization study.
Ciofani JL, Han D, Woolf B, Gill D, Allahwala UK, Bhindi R. Ciofani JL, et al. Int J Cardiol Heart Vasc. 2025 Jun 19;59:101729. doi: 10.1016/j.ijcha.2025.101729. eCollection 2025 Aug. Int J Cardiol Heart Vasc. 2025. PMID: 40606203 Free PMC article. No abstract available.
HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice.
Contreras RE, Gruber T, González-García I, Schriever SC, De Angelis M, Mallet N, Bernecker M, Legutko B, Kabra D, Schmidt M, Tschöp MH, Gutierrez-Aguilar R, Mellor J, García-Cáceres C, Pfluger PT. Contreras RE, et al. Mol Metab. 2024 Dec;90:102033. doi: 10.1016/j.molmet.2024.102033. Epub 2024 Sep 19. Mol Metab. 2024. PMID: 39304061 Free PMC article.
Adiposity and domain-specific stroke recovery: A Mendelian randomization study.
Wang M, Daghlas I, Aldridge CM, Zhang Z, Ren Y. Wang M, et al. Eur Stroke J. 2025 Feb 15:23969873251319916. doi: 10.1177/23969873251319916. Online ahead of print. Eur Stroke J. 2025. PMID: 39953957 Free PMC article.
Regulatory Roles of Long Noncoding RNAs in Arterial Stiffness and Hypertension.
Vargas JD, Abbas M, Goodney G, Le H, Hinton AO, Gaye A. Vargas JD, et al. Hypertension. 2025 Jul;82(7):1195-1207. doi: 10.1161/HYPERTENSIONAHA.124.23580. Epub 2025 May 29. Hypertension. 2025. PMID: 40438943 Free PMC article.

See all "Cited by" articles

References

1. Mills KT, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134:441–450. doi: 10.1161/CIRCULATIONAHA.115.018912. - DOI - PMC - PubMed
1. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788. doi: 10.1016/S0140-6736(18)32203-7. - DOI - PMC - PubMed
1. GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1923–1994. doi: 10.1016/S0140-6736(18)32225-6. - DOI - PMC - PubMed
1. Giri A, et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat. Genet. 2019;51:51–62. doi: 10.1038/s41588-018-0303-9. - DOI - PMC - PubMed
1. Evangelou E, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 2018;50:1412–1425. doi: 10.1038/s41588-018-0205-x. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

[1] Mills KT, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134:441–450. doi: 10.1161/CIRCULATIONAHA.115.018912. - DOI - PMC - PubMed

[2] Mills KT, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134:441–450. doi: 10.1161/CIRCULATIONAHA.115.018912. - DOI - PMC - PubMed

[3] GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788. doi: 10.1016/S0140-6736(18)32203-7. - DOI - PMC - PubMed

[4] GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788. doi: 10.1016/S0140-6736(18)32203-7. - DOI - PMC - PubMed

[5] GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1923–1994. doi: 10.1016/S0140-6736(18)32225-6. - DOI - PMC - PubMed

[6] GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1923–1994. doi: 10.1016/S0140-6736(18)32225-6. - DOI - PMC - PubMed

[7] Giri A, et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat. Genet. 2019;51:51–62. doi: 10.1038/s41588-018-0303-9. - DOI - PMC - PubMed

[8] Giri A, et al. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. Nat. Genet. 2019;51:51–62. doi: 10.1038/s41588-018-0303-9. - DOI - PMC - PubMed

[9] Evangelou E, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 2018;50:1412–1425. doi: 10.1038/s41588-018-0205-x. - DOI - PMC - PubMed

[10] Evangelou E, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat. Genet. 2018;50:1412–1425. doi: 10.1038/s41588-018-0205-x. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Collaborators

Affiliations

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical