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Nat Genet. 2019 Jan;51(1):51-62. doi: 10.1038/s41588-018-0303-9. Epub 2018 Dec 21.

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

Giri A1,2, Hellwege JN2,3, Keaton JM2,3, Park J4, Qiu C4, Warren HR5,6, Torstenson ES2,3, Kovesdy CP7, Sun YV8,9, Wilson OD2,10, Robinson-Cohen C10, Roumie CL11,12, Chung CP13, Birdwell KA10,14, Damrauer SM15,16, DuVall SL17,18, Klarin D19,20,21,22, Cho K23,24,25, Wang Y26, Evangelou E27,28, Cabrera CP5,6, Wain LV29,30, Shrestha R4, Mautz BS3, Akwo EA10, Sargurupremraj M31, Debette S31,32, Boehnke M33, Scott LJ33, Luan J34, Zhao JH34, Willems SM34, Thériault S35,36, Shah N37,38, Oldmeadow C39, Almgren P40, Li-Gao R41, Verweij N42, Boutin TS43, Mangino M44,45, Ntalla I5, Feofanova E46, Surendran P47, Cook JP48, Karthikeyan S47, Lahrouchi N21,49,50, Liu C51, Sepúlveda N52, Richardson TG53, Kraja A54,55,56, Amouyel P57, Farrall M58, Poulter NR59; Understanding Society Scientific Group; International Consortium for Blood Pressure; Blood Pressure-International Consortium of Exome Chip Studies, Laakso M60, Zeggini E61, Sever P62, Scott RA34, Langenberg C34, Wareham NJ34, Conen D63, Palmer CNA37, Attia J39,64, Chasman DI65, Ridker PM65, Melander O40, Mook-Kanamori DO41, Harst PV42, Cucca F66,67, Schlessinger D68, Hayward C43, Spector TD44, Jarvelin MR69,70,71,72,73, Hennig BJ74,75,76, Timpson NJ53, Wei WQ77, Smith JC77, Xu Y26,77, Matheny ME11,12,26,77, Siew EE10,12, Lindgren C21,78,79, Herzig KH80,81, Dedoussis G82, Denny JC77, Psaty BM83,84,85,86, Howson JMM47, Munroe PB5,6, Newton-Cheh C49, Caulfield MJ5,6, Elliott P69,87,88, Gaziano JM23,65, Concato J89,90, Wilson PWF91,92, Tsao PS93,94, Velez Edwards DR1,2,77, Susztak K4,95; Million Veteran Program, O'Donnell CJ65,96, Hung AM97,98, Edwards TL99,100.

Author information

1
Division of Quantitative Sciences, Department of Obstetrics & Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA.
2
Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
3
Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA.
4
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
5
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
6
National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
7
Nephrology Section, Memphis VA Medical Center, Memphis, TN, USA.
8
Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
9
Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
10
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
11
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
12
Geriatrics Research Education and Clinical Center, Tennessee Valley Health System, Veteran's Health Administration, Nashville, TN, USA.
13
Division of Rheumatology and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
14
Division of Nephrology, Department of Medicine, Nashville Veteran Affairs Hospital, Nashville, TN, USA.
15
Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
16
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
17
VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
18
University of Utah School of Medicine, Salt Lake City, UT, USA.
19
VA Boston Health Care System, Boston, MA, USA.
20
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
21
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
22
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
23
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
24
Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
25
Department of Medicine, Harvard Medical School, Boston, MA, USA.
26
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
27
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
28
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
29
Department of Health Sciences, University of Leicester, Leicester, UK.
30
National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
31
University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, Bordeaux, France.
32
Department of Neurology, Bordeaux University Hospital, Bordeaux, France.
33
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
34
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
35
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
36
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Quebec, Canada.
37
Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
38
Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan.
39
Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
40
Department of Clinical Sciences, Lund University, Malmö, Sweden.
41
Leiden University Medical Center, Leiden, the Netherlands.
42
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
43
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
44
Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
45
NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
46
Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
47
BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
48
Department of Biostatistics, University of Liverpool, Liverpool, UK.
49
Cardiovascular Research Center, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
50
Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
51
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
52
Immunology and Infection Department, London School of Hygiene & Tropical Medicine, London, UK.
53
MRC Integrative Epidemiology Unit (IEU), Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
54
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
55
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
56
Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
57
Risk Factors and Molecular Determinants of Aging-Related Diseases (RID-AGE), University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167, Lille, France.
58
Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, Oxford, UK.
59
International Centre for Circulatory Health, Imperial College London, London, UK.
60
University of Eastern Finland, School of Medicine, Kuopio, Finland.
61
Wellcome Trust Sanger Institute, Hinxton, UK.
62
National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London, UK.
63
Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
64
Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia.
65
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
66
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.
67
Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
68
Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA.
69
MRC-PHE Centre for Environment & Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
70
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
71
Biocenter Oulu, University of Oulu, Oulu, Finland.
72
Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
73
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, Middlesex, UK.
74
Wellcome Trust, London, UK.
75
MRC Unit The Gambia, Atlantic Boulevard, Fajara, Banjul, The Gambia.
76
London School of Hygiene & Tropical Medicine, London, UK.
77
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
78
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
79
Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
80
Institute of Biomedicine, Biocenter of Oulu, Medical Research Center, Oulu University and Oulu University Hospital, Oulu, Finland.
81
Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
82
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
83
Departments of Medicine, University of Washington, Seattle, WA, USA.
84
Departments of Epidemiology, University of Washington, Seattle, WA, USA.
85
Departments of Health Services, University of Washington, Seattle, WA, USA.
86
Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
87
National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
88
UK Dementia Research Institute at Imperial College London, London, UK.
89
Clinical Epidemiology Research Center (CERC), VA Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, CT, USA.
90
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
91
Atlanta VA Medical Center, Atlanta, GA, USA.
92
Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
93
VA Palo Alto Health Care System, Palo Alto, CA, USA.
94
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
95
Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
96
VA Boston Healthcare, Section of Cardiology and Department of Medicine, Boston, MA, USA.
97
Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA. adriana.hung@vanderbilt.edu.
98
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. adriana.hung@vanderbilt.edu.
99
Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu.
100
Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu.

Abstract

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

PMID:
30578418
DOI:
10.1038/s41588-018-0303-9

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