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Nat Genet. 2016 Oct;48(10):1151-1161. doi: 10.1038/ng.3654. Epub 2016 Sep 12.

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

Surendran P#1, Drenos F#2,3, Young R#1, Warren H#4,5, Cook JP#6,7, Manning AK#8,9,10, Grarup N#11, Sim X#12,13,14, Barnes DR1, Witkowska K4,5, Staley JR1, Tragante V15, Tukiainen T8,9,16, Yaghootkar H17, Masca N18,19, Freitag DF1, Ferreira T20, Giannakopoulou O21, Tinker A21,5, Harakalova M15, Mihailov E22, Liu C23, Kraja AT24,25, Fallgaard Nielsen S26, Rasheed A27, Samuel M27, Zhao W28, Bonnycastle LL29, Jackson AU13,12, Narisu N29, Swift AJ29, Southam L30,20, Marten J31, Huyghe JR13,12, Stančáková A32, Fava C33,34, Ohlsson T33, Matchan A30, Stirrups KE21,35, Bork-Jensen J11, Gjesing AP11, Kontto J36, Perola M36,37,22, Shaw-Hawkins S4, Havulinna AS36, Zhang H38, Donnelly LA39, Groves CJ40, Rayner NW40,20,30, Neville MJ40,41, Robertson NR20,40, Yiorkas AM42,43, Herzig KH44,45, Kajantie E36,46,47, Zhang W48,49, Willems SM50, Lannfelt L51, Malerba G52, Soranzo N53,35,54, Trabetti E52, Verweij N55,9,56, Evangelou E48,57, Moayyeri A48,58, Vergnaud AC48, Nelson CP18,19, Poveda A59,60, Varga TV59, Caslake M61, de Craen AJ62,63, Trompet S62,64, Luan J50, Scott RA50, Harris SE65,66, Liewald DC65,67, Marioni R65,66,68, Menni C69, Farmaki AE70, Hallmans G71, Renström F59,71, Huffman JE31,23, Hassinen M72, Burgess S1, Vasan RS23,73,74, Felix JF75; CHARGE-Heart Failure Consortium, Uria-Nickelsen M76, Malarstig A77, Reily DF78, Hoek M79, Vogt T79,80, Lin H23,81, Lieb W82; EchoGen Consortium, Traylor M83, Markus HF83; METASTROKE Consortium, Highland HM84, Justice AE84, Marouli E21; GIANT Consortium, Lindström J36, Uusitupa M85,86, Komulainen P72, Lakka TA72,87,88, Rauramaa R72,88, Polasek O89,90, Rudan I89, Rolandsson O91, Franks PW59,91,92, Dedoussis G70, Spector TD69; EPIC-InterAct Consortium, Jousilahti P36, Männistö S36, Deary IJ65,67, Starr JM65,93, Langenberg C50, Wareham NJ50, Brown MJ4, Dominiczak AF94, Connell JM39, Jukema JW64,95, Sattar N94, Ford I61, Packard CJ61, Esko T22,96,8,9, Mägi R22, Metspalu A22,97, de Boer RA98, van der Meer P98, van der Harst P98,99,100; Lifelines Cohort Study, Gambaro G101, Ingelsson E102,103, Lind L102, de Bakker PI104,105, Numans ME106,105, Brandslund I107,108, Christensen C109, Petersen ER110, Korpi-Hyövälti E111, Oksa H112, Chambers JC48,49,113, Kooner JS49,114,113, Blakemore AI42,43, Franks S115, Jarvelin MR116,117,118,119, Husemoen LL120, Linneberg A120,121,122, Skaaby T120, Thuesen B120, Karpe F40,41, Tuomilehto J36,123,124,125, Doney AS39, Morris AD126, Palmer CN39, Holmen OL127,128, Hveem K127,129, Willer CJ38,130,131, Tuomi T132,133, Groop L134,133, Käräjämäki A135,136, Palotie A16,9,133,137, Ripatti S133,138,30, Salomaa V36, Alam DS139, Shafi Majumder AA140, Di Angelantonio E1,54, Chowdhury R1, McCarthy MI40,41,20, Poulter N141, Stanton AV142, Sever P141, Amouyel P143,144,145,146, Arveiler D147, Blankenberg S148,149, Ferrières J150, Kee F151, Kuulasmaa K36, Müller-Nurasyid M152,153,154, Veronesi G155, Virtamo J36, Deloukas P21,156; Wellcome Trust Case Control Consortium, Elliott P116; Understanding Society Scientific Group, Zeggini E30, Kathiresan S56,157,158,9, Melander O33, Kuusisto J32, Laakso M32, Padmanabhan S94, Porteous D66, Hayward C31, Scotland G159, Collins FS29, Mohlke KL160, Hansen T11, Pedersen O11, Boehnke M13,12, Stringham HM13,12; EPIC-CVD Consortium, Frossard P27, Newton-Cheh C56,157; CHARGE+ Exome Chip Blood Pressure Consortium, Tobin MD6, Nordestgaard BG26; T2D-GENES Consortium; GoT2DGenes Consortium; ExomeBP Consortium; CHD Exome+ Consortium, Caulfield MJ4,5, Mahajan A20, Morris AP20,7, Tomaszewski M18,19,161, Samani NJ18,19, Saleheen D#28,27,1, Asselbergs FW#15,100,162, Lindgren CM#163,9,20, Danesh J#1,164,54, Wain LV#6, Butterworth AS#1,165, Howson JM#1, Munroe PB#4,5.

Author information

1
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
2
Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
3
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, Rayne Building University College London, London, UK.
4
Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.
5
National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
6
Department of Health Sciences, University of Leicester, Leicester, UK.
7
Department of Biostatistics, University of Liverpool, Liverpool, UK.
8
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
9
Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts, USA.
10
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
11
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
12
Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
13
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
14
Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore.
15
Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
16
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
17
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
18
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
19
National Institute for Health Research Leicester Biomedical Research Unit in Cardiovascular Disease, Leicester, UK.
20
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
21
Heart Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
22
Estonian Genome Center, University of Tartu, Tartu, Estonia.
23
National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA.
24
Division of Statistical Genomics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
25
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
26
Department of Clinical Biochemistry Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
27
Centre for Non-Communicable Diseases, Karachi, Pakistan.
28
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
29
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
30
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
31
Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
32
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
33
University of Lund, Department of Clinical Sciences, Malmö, Sweden.
34
University of Verona, Department of Medicine, Verona, Italy.
35
Department of Haematology, University of Cambridge, Cambridge, UK.
36
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
37
Institute of Molecular Medicine FIMM, University of Helsinki, Finland.
38
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA.
39
Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
40
Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
41
National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, Oxford, UK.
42
Section of Investigative Medicine, Imperial College London, London, UK.
43
Department of Life Sciences, Brunel University London, London, UK.
44
Institute of Biomedicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
45
Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
46
Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
47
Department of Obstetrics and Gynaecology, Oulu University Hospital and University of Oulu, Oulu, Finland.
48
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
49
Department of Cardiology, Ealing Hospital, Middlesex, UK.
50
Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
51
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
52
Section of Biology and Genetics, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
53
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
54
The National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
55
University Medical Center Groningen, University of Groningen, Department of Cardiology, The Netherlands.
56
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
57
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
58
Farr Institute of Health Informatics Research, Institute of Health Informatics, University College London, London, UK.
59
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
60
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
61
University of Glasgow, Glasgow, UK.
62
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
63
Mr. De Craen suddenly passed away January 2016.
64
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
65
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
66
Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
67
Department of Psychology, University of Edinburgh, Edinburgh, UK.
68
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
69
Department of Twin Research and Genetic Epidemiology, King's College London, UK.
70
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
71
Department of Biobank Research, Umeå University, Umeå, Sweden.
72
Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
73
Section of Cardiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
74
Sections of Preventive Medicine and Epidemiology, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
75
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
76
Development Management and Planning, Pfizer Worldwide Research and Development.
77
Pfizer Worldwide Research and Development, Stockholm, Sweden.
78
Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts, USA.
79
Merck Research Laboratories, Cardiometabolic Disease, Kenilworth, New Jersey, USA.
80
CHDI Management/CHDI Foundation, Princeton, New Jersey, USA.
81
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
82
Institute of Epidemiology and Biobank Popgen, Kiel University, Kiel, Germany.
83
Neurology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
84
University of North Carolina at Chapel Hill, Department of Epidemiology, Chapel Hill, North Carolina, USA.
85
Department of Public Health and Clinical Nutrition, University of Eastern Finland, Finland.
86
Research Unit, Kuopio University Hospital, Kuopio, Finland.
87
Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Finland.
88
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
89
Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
90
Faculty of Medicine, University of Split, Croatia.
91
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
92
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
93
Alzheimer Scotland Research Centre, University of Edinburgh, Edinburgh, UK.
94
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
95
The Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
96
Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
97
Institute of Molecular and Cell Biology, Tartu, Estonia.
98
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
99
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
100
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
101
Division of Nephrology, Department of Internal Medicine and Medical Specialties, Columbus - Gemelli University Hospital, Catholic University, Rome, Italy.
102
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
103
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
104
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
105
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
106
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
107
Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
108
Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
109
Medical Department, Lillebaelt Hospital, Vejle, Denmark.
110
Department of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
111
South Ostrobothnia Central Hospital, Seinäjoki, Finland.
112
Tampere University Hospital, Tampere, Finland.
113
Imperial College Healthcare NHS Trust, London, UK.
114
National Heart and Lung Institute, Imperial College London, London, UK.
115
Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.
116
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.
117
Centre for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland.
118
Biocenter Oulu, University of Oulu, Oulu, Finland.
119
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
120
Research Centre for Prevention and Health, Capital Region of Denmark, Copenhagen, Denmark.
121
Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark.
122
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
123
Dasman Diabetes Institute, Dasman, Kuwait.
124
Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
125
King Abdulaziz University, Jeddah, Saudi Arabia.
126
School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, UK.
127
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.
128
St. Olav Hospital, Trondheim University Hospital, Trondheim, Norway.
129
Department of Medicine, Levanger Hospital, Nord- Trøndelag Health Trust, Levanger, Norway.
130
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
131
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
132
Folkhälsan Research Centre, Helsinki, Finland; Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
133
Institute for Molecular Medicine Finland University of Helsinki, Helsinki, Finland.
134
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
135
Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland.
136
Diabetes Center, Vaasa Health Care Center, Vaasa, Finland.
137
Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
138
Department of Public Health, University of Helsinki, Finland.
139
ICDDR, B; Mohakhali, Dhaka, Bangladesh.
140
National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Dhaka, Bangladesh.
141
International Centre for Circulatory Health, Imperial College London, UK.
142
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
143
University of Lille, UMR1167, Risk Factors and Molecular Determinants of aging-related diseases, Lille, France.
144
Inserm, Lille, France.
145
Centre Hospitalier Universitaire Lille, Public Health, Lille, France.
146
Institut Pasteur de Lille, Lille, France.
147
Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France.
148
Department of General and Interventional Cardiology, University Heart Center Hamburg, Germany.
149
University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
150
Department of Epidemiology, UMR 1027- INSERM, Toulouse University-CHU Toulouse, Toulouse, France.
151
Director, UKCRC Centre of Excellence for Public Health, Queens University, Belfast, Northern Ireland.
152
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
153
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
154
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
155
Research Center in Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
156
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
157
Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
158
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
159
A Collaboration between the University Medical Schools and NHS, Aberdeen, Dundee, Edinburgh and Glasgow, UK.
160
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
161
Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
162
Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK.
163
The Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
164
Wellcome Trust Sanger Institute, Hinxton, UK.
165
The National Institute for Health Research Blood and Transplant Research.
#
Contributed equally

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.

PMID:
27618447
PMCID:
PMC5056636
DOI:
10.1038/ng.3654
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of 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 Grant-Merck, Bayer, Aegerion; SAB-Catabasis, Regeneron Genetics Center, Merck, Celera; Equity-San Therapeutics, Catabasis; Consulting-Novartis, Aegerion, Bristol Myers-Squibb, Sanofi, AstraZeneca, Alnylam. P. Sever has received research awards from Pfizer Inc. A. Malarstig and M. Uria-Nickelsen are full time employees of Pfizer. D. Reily and M. Hoek are full time employees of Merck and co Inc. M.J. Caulfield is Chief Scientist for Genomics England a UK Government company. The authors declare no competing financial interest.

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