Genome-wide association study identifies eight loci associated with blood pressure
From: Nature Genetics Nature Genetics 41, 666 - 676 (2009)
Published online: 10 May 2009 | doi:10.1038/ng.361

Christopher Newton-Cheh1,2,3,94, Toby Johnson4,5,6,94, Vesela Gateva7,94, Martin D Tobin8,94, Murielle Bochud5, Lachlan Coin9, Samer S Najjar10, Jing Hua Zhao11,12, Simon C Heath13, Susana Eyheramendy14,15, Konstantinos Papadakis16, Benjamin F Voight1,3, Laura J Scott7, Feng Zhang17, Martin Farrall18,19, Toshiko Tanaka20,21, Chris Wallace22,23,24, John C Chambers9, Kay-Tee Khaw12,25, Peter Nilsson26, Pim van der Harst27, Silvia Polidoro28, Diederick E Grobbee29, N Charlotte Onland-Moret29,30, Michiel L Bots29, Louise V Wain8, Katherine S Elliott19, Alexander Teumer31, Jian'an Luan11, Gavin Lucas32, Johanna Kuusisto33, Paul R Burton8, David Hadley16, Wendy L McArdle34, Wellcome Trust Case Control Consortium93, Morris Brown35, Anna Dominiczak36, Stephen J Newhouse22,23, Nilesh J Samani37, John Webster38, Eleftheria Zeggini19,39, Jacques S Beckmann4,40, Sven Bergmann4,6, Noha Lim41, Kijoung Song41, Peter Vollenweider42, Gerard Waeber42, Dawn M Waterworth41, Xin Yuan41, Leif Groop43,44, Marju Orho-Melander26, Alessandra Allione28, Alessandra Di Gregorio28,45, Simonetta Guarrera28, Salvatore Panico46, Fulvio Ricceri28, Valeria Romanazzi28,45, Carlotta Sacerdote47, Paolo Vineis9,28, Inês Barroso12,39, Manjinder S Sandhu11,12,25, Robert N Luben12,25, Gabriel J Crawford3, Pekka Jousilahti48, Markus Perola48,49, Michael Boehnke7, Lori L Bonnycastle50, Francis S Collins50, Anne U Jackson7, Karen L Mohlke51, Heather M Stringham7, Timo T Valle52, Cristen J Willer7, Richard N Bergman53, Mario A Morken50, Angela Döring15, Christian Gieger15, Thomas Illig15, Thomas Meitinger54,55, Elin Org56, Arne Pfeufer54,55, H Erich Wichmann15,57, Sekar Kathiresan1,2,3, Jaume Marrugat32, Christopher J O'Donnell58,59, Stephen M Schwartz60,61, David S Siscovick60,61, Isaac Subirana32,62, Nelson B Freimer63, Anna-Liisa Hartikainen64, Mark I McCarthy19,65,66, Paul F O'Reilly9, Leena Peltonen39,49, Anneli Pouta64,67, Paul E de Jong68, Harold Snieder69, Wiek H van Gilst27, Robert Clarke70, Anuj Goel18,19, Anders Hamsten71, John F Peden18,19, Udo Seedorf72, Ann-Christine Syvänen73, Giovanni Tognoni74, Edward G Lakatta10, Serena Sanna75, Paul Scheet76, David Schlessinger77, Angelo Scuteri78, Marcus Dörr79, Florian Ernst31, Stephan B Felix79, Georg Homuth31, Roberto Lorbeer80, Thorsten Reffelmann79, Rainer Rettig81, Uwe Völker31, Pilar Galan82, Ivo G Gut13, Serge Hercberg82, G Mark Lathrop13, Diana Zelenika13, Panos Deloukas12,39, Nicole Soranzo17,39, Frances M Williams17, Guangju Zhai17, Veikko Salomaa48, Markku Laakso33, Roberto Elosua32,62, Nita G Forouhi11, Henry Völzke80, Cuno S Uiterwaal29, Yvonne T van der Schouw29, Mattijs E Numans29, Giuseppe Matullo28,45, Gerjan Navis68, Göran Berglund26, Sheila A Bingham12,83, Jaspal S Kooner84, John M Connell36, Stefania Bandinelli85, Luigi Ferrucci21, Hugh Watkins18,19, Tim D Spector17, Jaakko Tuomilehto52,86,87, David Altshuler1,3,88,89, David P Strachan16, Maris Laan56, Pierre Meneton90, Nicholas J Wareham11,12, Manuela Uda75, Marjo-Riitta Jarvelin9,67,91, Vincent Mooser41, Olle Melander26, Ruth JF Loos11,12, Paul Elliott9,94, Gonçalo R Abecasis92,94, Mark Caulfield22,23,94 & Patricia B Munroe22,23,94

Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N less than or equal to 71,225 European ancestry, N less than or equal to 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 times 10-24), CYP1A2 (P = 1 times 10-23), FGF5 (P = 1 times 10-21), SH2B3 (P = 3 times 10-18), MTHFR (P = 2 times 10-13), c10orf107 (P = 1 times 10-9), ZNF652 (P = 5 times 10-9) and PLCD3 (P = 1 times 10-8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

1. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
2. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
3. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
4. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
5. University Institute for Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland.
6. Swiss Institute of Bioinformatics, Lausanne, Switzerland.
7. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
8. Departments of Health Sciences and Genetics, Adrian Building, University of Leicester, University Road, Leicester, UK.
9. Department of Epidemiology and Public Health, Imperial College London, St. Mary's Campus, Norfolk Place, London, UK.
10. Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
11. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
12. Cambridge-Genetics of Energy Metabolism (GEM) Consortium, Cambridge, UK.
13. Centre National de Génotypage, Evry Cedex, France.
14. Pontificia Universidad Católica de Chile, Facultad de Matemáticas, Santiago, Chile.
15. Institute of Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
16. Division of Community Health Sciences, St. George's, University of London, London, UK.
17. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
18. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
19. The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, UK.
20. Medstar Research Institute, Baltimore, Maryland, USA.
21. Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.
22. Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
23. The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
24. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK.
25. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
26. Department of Clinical Sciences, Lund University, Malmö University Hospital, Malmö, Sweden.
27. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
28. ISI Foundation (Institute for Scientific Interchange), Villa Gualino, Torino, Italy.
29. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
30. Complex Genetics Section, Department of Medical Genetics-DBG, University Medical Center Utrecht, Utrecht, The Netherlands.
31. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
32. Cardiovascular Epidemiology and Genetics, Institut Municipal d'Investigació Mèdica, Barcelona, Spain.
33. Department of Medicine, University of Kuopio, Kuopio, Finland.
34. ALSPAC Laboratory, Department of Social Medicine, University of Bristol, Bristol, UK.
35. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
36. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
37. Department of Cardiovascular Science, University of Leicester, Glenfield Hospital, Leicester, UK.
38. Aberdeen Royal Infirmary, Aberdeen, UK.
39. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
40. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
41. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
42. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
43. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital, Malmö, Sweden.
44. Lund University, Malmö, Sweden.
45. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
46. Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
47. Unit of Cancer Epidemiology, University of Turin and Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Turin, Italy.
48. National Institute for Welfare and Health, Helsinki, Finland.
49. Institute for Molecular Medicine Finland FIMM, University of Helsinki and National Public Health Institute, Finland.
50. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
51. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
52. Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland.
53. Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles, California, USA.
54. Institute of Human Genetics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany.
55. Institute of Human Genetics, Technische Universität München, Munich, Germany.
56. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
57. Ludwig Maximilians University, IBE, Chair of Epidemiology, Munich, Germany.
58. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
59. Framingham Heart Study and National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.
60. Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA.
61. Department of Epidemiology, University of Washington, Seattle, Washington, USA.
62. CIBER Epidemiología y Salud Pública, Barcelona, Spain.
63. Center for Neurobehavioral Genetics, Gonda Center, University of California Los Angeles, Los Angeles, California, USA.
64. Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland.
65. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.
66. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
67. Department of Child and Adolescent Health, National Public Health Institute (KTL), Oulu, Finland.
68. Division of Nephrology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
69. Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
70. Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK.
71. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
72. Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany.
73. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
74. Consorzio Mario Negri Sud, Via Nazionale, Santa Maria Imbaro (Chieti), Italy.
75. Istituto di Neurogenetica e Neurofarmacologia, CNR, Monserrato, Cagliari, Italy.
76. Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
77. Laboratory of Genetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
78. Unitá Operativa Geriatria, Istituto Nazionale Ricovero e Cura per Anziani (INRCA) IRCCS, Rome, Italy.
79. Department of Internal Medicine B, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
80. Institute for Community Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
81. Institute of Physiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
82. U557 Institut National de la Santé et de la Recherche Médicale, U1125 Institut National de la Recherche Agronomique, Université Paris 13, Bobigny Cedex, France.
83. MRC Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Cambridge, UK.
84. National Heart and Lung Institute, Imperial College London, London, UK.
85. Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
86. Department of Public Health, University of Helsinki, Helsinki, Finland.
87. South Ostrobothnia Central Hospital, Seinäjoki, Finland.
88. Department of Medicine and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
89. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
90. U872 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Paris Descartes, Paris Cedex, France.
91. Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland.
92. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
93. A full list of authors is provided in the Supplementary Note online.
94. These authors contributed equally to this work.

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Genome-wide association study of blood pressure and hypertension

Nature Genetics 41, 677 - 687 (2009)
Published online: 10 May 2009 | Corrected online: 17 May 2009 | doi:10.1038/ng.384

Daniel Levy1,2,29, Georg B Ehret3,4,29, Kenneth Rice5,29, Germaine C Verwoert6,7,28,29, Lenore J Launer8,29, Abbas Dehghan6, Nicole L Glazer9, Alanna C Morrison10, Andrew D Johnson1,2, Thor Aspelund11,12, Yurii Aulchenko6, Thomas Lumley5, Anna Köttgen13, Ramachandran S Vasan1,14,15,16,17, Fernando Rivadeneira6,7, Gudny Eiriksdottir11, Xiuqing Guo18, Dan E Arking3, Gary F Mitchell19, Francesco U S Mattace-Raso6,20, Albert V Smith11, Kent Taylor18, Robert B Scharpf21, Shih-Jen Hwang1,2, Eric J G Sijbrands7, Joshua Bis9, Tamara B Harris8, Santhi K Ganesh3,22, Christopher J O'Donnell1,2, Albert Hofman6, Jerome I Rotter18, Josef Coresh13, Emelia J Benjamin1,14,15,16,17, André G Uitterlinden6,7, Gerardo Heiss23, Caroline S Fox1,2, Jacqueline C M Witteman6,28, Eric Boerwinkle10, Thomas J Wang1,24, Vilmundur Gudnason11,12,29, Martin G Larson1,25,29, Aravinda Chakravarti3,13,29, Bruce M Psaty26,27,29 & Cornelia M van Duijn6,29

Abstract

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 times 10-7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 times 10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
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1. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
2. Center for Population Studies, NHLBI, Bethesda, Maryland, USA.
3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
4. Division of Cardiology, Geneva University Hospital, Geneva, Switzerland.
5. Department of Biostatistics, University of Washington, Seattle, Washington, USA.
6. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
7. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
8. National Institute of Aging's Laboratory for Epidemiology, Demography, and Biometry, Bethesda, Maryland, USA.
9. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA.
10. Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
11. Icelandic Heart Association, Kopavogur, Iceland.
12. University of Iceland, Reykjavik, Iceland.
13. Department of Epidemiology and Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
14. Department of Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA.
15. Department of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
16. Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
17. Epidemiology Section, Boston University School of Public Health, Boston, Massachusetts, USA.
18. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
19. Cardiovascular Engineering, Inc., Norwood, Massachusetts, USA.
20. Department of Internal Medicine, Section of Geriatric Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
21. Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA.
22. National Human Genome Research Institute, Vascular Biology Section, Bethesda, Maryland, USA.
23. Carolina Cardiovascular Biology Center, Chapel Hill, North Carolina, USA.
24. Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
25. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.
26. Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, Washington, USA.
27. Center for Health Studies, Group Health, Seattle, Washington, USA.
28. Member of the Netherlands Consortium on Healthy Aging (NCHA), The Netherlands.
29. These authors contributed equally to this work.

Correspondence to: Daniel Levy1,2,29 e-mail: levyd@nhlbi.nih.gov

Correspondence to: Cornelia M van Duijn6,29 e-mail: c.vanduijn@erasmusmc.nl
* NOTE: In the version of this article initially published online, the respective exponents of the P values for association of rs8096897 and rs880315 with SBP were transposed. The error has been corrected for the print, PDF and HTML versions of this article.