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PLoS One. 2018 Jun 18;13(6):e0198166. doi: 10.1371/journal.pone.0198166. eCollection 2018.

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

Feitosa MF1, Kraja AT1, Chasman DI2,3, Sung YJ4, Winkler TW5, Ntalla I6, Guo X7, Franceschini N8, Cheng CY9,10,11, Sim X12, Vojinovic D13, Marten J14, Musani SK15, Li C16, Bentley AR17, Brown MR18, Schwander K4, Richard MA19, Noordam R20, Aschard H21,22, Bartz TM23, Bielak LF24, Dorajoo R25, Fisher V26, Hartwig FP27,28, Horimoto ARVR29, Lohman KK30, Manning AK31,32, Rankinen T33, Smith AV34,35, Tajuddin SM36, Wojczynski MK1, Alver M37, Boissel M38, Cai Q39, Campbell A40, Chai JF12, Chen X41, Divers J30, Gao C42, Goel A43,44, Hagemeijer Y45, Harris SE46,47, He M48, Hsu FC30, Jackson AU49, Kähönen M50,51, Kasturiratne A52, Komulainen P53, Kühnel B54,55, Laguzzi F56, Luan J57, Matoba N58, Nolte IM59, Padmanabhan S60, Riaz M61,62, Rueedi R63,64, Robino A65, Said MA45, Scott RA57, Sofer T32,66, Stančáková A67, Takeuchi F68, Tayo BO69, van der Most PJ59, Varga TV70, Vitart V14, Wang Y71, Ware EB72, Warren HR6,73, Weiss S74,75, Wen W39, Yanek LR76, Zhang W77,78, Zhao JH57, Afaq S77, Amin N13, Amini M59, Arking DE79, Aung T9,10,11, Boerwinkle E80,81, Borecki I1, Broeckel U82, Brown M6,73, Brumat M83, Burke GL84, Canouil M38, Chakravarti A79, Charumathi S9,10, Ida Chen YD7, Connell JM85, Correa A15, de Las Fuentes L4,86, de Mutsert R87, de Silva HJ88, Deng X26, Ding J89, Duan Q90, Eaton CB91, Ehret G92, Eppinga RN45, Evangelou E77,93, Faul JD72, Felix SB75,94, Forouhi NG57, Forrester T95, Franco OH13, Friedlander Y96, Gandin I83, Gao H77, Ghanbari M13,97, Gigante B56, Gu CC4, Gu D98, Hagenaars SP46,99, Hallmans G100, Harris TB101, He J102,103, Heikkinen S67,104, Heng CK105,106, Hirata M107, Howard BV108,109, Ikram MA13,110,111; InterAct Consortium, John U75,112, Katsuya T113,114, Khor CC25,115, Kilpeläinen TO116,117, Koh WP12,118, Krieger JE29, Kritchevsky SB119, Kubo M120, Kuusisto J67, Lakka TA53,104,121, Langefeld CD30, Langenberg C57, Launer LJ101, Lehne B77, Lewis CE122, Li Y4, Lin S1, Liu J12,25, Liu J123, Loh M77,124, Louie T125, Mägi R37, McKenzie CA95, Meitinger T126,127, Metspalu A37, Milaneschi Y128, Milani L37, Mohlke KL90, Momozawa Y129, Nalls MA130,131, Nelson CP61,62, Sotoodehnia N132, Norris JM133, O'Connell JR134,135, Palmer ND136, Perls T137, Pedersen NL41, Peters A55,138, Peyser PA24, Poulter N139, Raffel LJ140, Raitakari OT141,142, Roll K7, Rose LM2, Rosendaal FR87, Rotter JI7, Schmidt CO143, Schreiner PJ144, Schupf N145, Scott WR77,146, Sever PS146, Shi Y9, Sidney S147, Sims M15, Sitlani CM148, Smith JA24,72, Snieder H59, Starr JM46,149, Strauch K150,151, Stringham HM49, Tan NYQ9, Tang H152, Taylor KD7, Teo YY12,25,153,154,155, Tham YC9, Turner ST156, Uitterlinden AG13,157, Vollenweider P158, Waldenberger M54,55, Wang L1, Wang YX159,160, Wei WB160, Williams C1, Yao J7, Yu C48, Yuan JM161,162, Zhao W24, Zonderman AB163, Becker DM76, Boehnke M49, Bowden DW136, Chambers JC77,78,164,165,166, Deary IJ46,99, Esko T37,167, Farrall M43,44, Franks PW70,168, Freedman BI169, Froguel P38,170, Gasparini P65,83, Gieger C54,171, Jonas JB159,172, Kamatani Y58, Kato N68, Kooner JS78,146,165,166, Kutalik Z64,173, Laakso M67, Laurie CC125, Leander K56, Lehtimäki T174,175, Study LC176, Magnusson PKE41, Oldehinkel AJ177, Penninx BWJH128, Polasek O178,179,180, Porteous DJ40, Rauramaa R53, Samani NJ61,62, Scott J146, Shu XO39, van der Harst P45,181, Wagenknecht LE84, Wareham NJ57, Watkins H43,44, Weir DR72, Wickremasinghe AR52, Wu T48, Zheng W39, Bouchard C33, Christensen K182, Evans MK36, Gudnason V34,35, Horta BL27, Kardia SLR24, Liu Y183, Pereira AC29, Psaty BM184,185, Ridker PM2,3, van Dam RM12,186, Gauderman WJ187, Zhu X71, Mook-Kanamori DO87,188, Fornage M18,19, Rotimi CN17, Cupples LA26,189, Kelly TN102, Fox ER190, Hayward C14, van Duijn CM13, Tai ES12,118,186, Wong TY9,10,11, Kooperberg C191, Palmas W192, Rice K125, Morrison AC18, Elliott P166, Caulfield MJ6,73, Munroe PB6,73, Rao DC4, Province MA1, Levy D189,193.

Author information

1
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
2
Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
3
Harvard Medical School, Boston, Massachusetts, United States of America.
4
Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
5
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
6
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
7
Genomic Outcomes, Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California, United States of America.
8
Epidemiology, University of North Carolina Gilling School of Global Public Health, Chapel Hill, North Carolina, United States of America.
9
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.
10
Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
11
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
12
Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore.
13
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
14
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
15
Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
16
Epidemiology and Biostatistics, University of Georgia at Athens College of Public Health, Athens, Georgia, United States of America.
17
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
18
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
19
Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
20
Internal Medicine, Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
21
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
22
Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France.
23
Cardiovascular Health Research Unit, Biostatistics and Medicine, University of Washington, Seattle, Washington, United States of America.
24
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America.
25
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore.
26
Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
27
Postgraduate Programme in Epidemiology, Federal University of Pelotas, Pelotas, RS, Brazil.
28
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
29
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, Brazil.
30
Biostatistical Sciences, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
31
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
32
Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
33
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States of America.
34
Icelandic Heart Association, Kopavogur, Iceland.
35
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
36
Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
37
Estonian Genome Center, University of Tartu, Tartu, Estonia.
38
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille, France.
39
Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
40
Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
41
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Stockholm, Sweden.
42
Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
43
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, Oxfordshire, United Kingdom.
44
Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, United Kingdom.
45
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
46
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom.
47
Medical Genetics Section, Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
48
Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health for Incubating, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
49
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
50
Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
51
University of Tampere, Tampere, Finland.
52
Department of Public Health, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
53
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
54
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
55
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
56
Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
57
MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
58
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
59
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
60
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
61
Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.
62
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom.
63
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
64
Swiss Instititute of Bioinformatics, Lausanne, Switzerland.
65
Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
66
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, United States of America.
67
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
68
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
69
Department of Public Health Sciences, Loyola University Chicago, Maywood, Illinois, United States of America.
70
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
71
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
72
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, United States of America.
73
NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, London, United Kingdom.
74
Interfaculty Institute for Genetics and Functional genomics, University Medicine Ernst Moritz Arndt University Greifsald, Greifswald, Germany.
75
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
76
Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
77
Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
78
Department of Cardiology, Ealing Hospital, Middlesex, United Kingdom.
79
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
80
Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, Texas, United States of America.
81
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
82
Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
83
Department of Medical Sciences, University of Trieste, Trieste, Italy.
84
Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
85
Ninewells Hospital & Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
86
Cardiovascular Division, Department of Medicine, Washington University, St. Louis, Missouri, United States of America.
87
Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
88
Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
89
Center on Diabetes, Obesity, and Metabolism, Gerontology and Geriatric Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
90
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
91
Department of Family Medicine and Epidemiology, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
92
Cardiology, Geneva University Hospital, Geneva, Switzerland.
93
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
94
Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
95
The Caribbean Institute for Health Research (CAIHR), University of the West Indies, Mona, Jamaica.
96
Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
97
Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
98
Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
99
Psychology, The University of Edinburgh, Edinburgh, United Kingdom.
100
Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Västerbotten, Sweden.
101
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
102
Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, United States of America.
103
Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
104
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Finland.
105
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
106
Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
107
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.
108
MedStar Health Research Institute, Hyattsville, Maryland, United States of America.
109
Center for Clinical and Translational Sciences and Department of Medicine, Georgetown-Howard Universities, Washington, DC, United States of America.
110
Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
111
Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
112
Institute of Social Medicine and Prevention, University Medicine Greifswald, Greifswald, Germany.
113
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
114
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
115
Department of Biochemistry, National University of Singapore, Singapore, Singapore.
116
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
117
Department of Environmental Medicine and Public Health, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
118
Duke-NUS Medical School, Singapore, Singapore.
119
Sticht Center for Healthy Aging and Alzheimer's Prevention, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
120
Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
121
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
122
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
123
WHI CCC, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
124
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore.
125
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
126
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
127
Institute of Human Genetics, Technische Universität München, Munich, Germany.
128
Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
129
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
130
Data Tecnica International, Glen Echo, Maryland, United States of America.
131
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, United States of America.
132
Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, Washington, United States of America.
133
Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, United States of America.
134
Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
135
Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
136
Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
137
Geriatrics Section, Boston University Medical Center, Boston, Massachusetts, United States of America.
138
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Neuherberg, Germany.
139
School of Public Health, Imperial College London, London, London, United Kingdom.
140
Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, California, United States of America.
141
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
142
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
143
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
144
Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
145
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, United States of America.
146
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
147
Division of Research, Kaiser Permanente of Northern California, Oakland, California, United States of America.
148
Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, Washington, United States of America.
149
Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom.
150
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
151
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU, Munich, Germany.
152
Department of Genetics, Stanford University, Stanford, California, United States of America.
153
Life Sciences Institute, National University of Singapore, Singapore, Singapore.
154
NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore.
155
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
156
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America.
157
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
158
Service of Internal Medicine, Department of Internal Medicine, University Hospital, Lausanne, Switzerland.
159
Beijing Institute of Ophthalmology, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Eye Center, Capital Medical University, Beijing, China.
160
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
161
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
162
Division of Cancer Control and Population Sciences, UPMC Hillman Cancer, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
163
Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
164
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
165
Imperial College Healthcare NHS Trust, London, United Kingdom.
166
MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
167
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, United States of America.
168
Harvard T. H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, Massachusetts, United States of America.
169
Nephrology, Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
170
Department of Genomics of Common Disease, Imperial College London, London, United Kingdom.
171
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
172
Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany, Germany.
173
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
174
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
175
Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
176
Lifelines Cohort, Groningen, The Netherlands.
177
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
178
Department of Public Health, Department of Medicine, University of Split, Split, Croatia.
179
Psychiatric Hospital "Sveti Ivan", Zagreb, Croatia.
180
Gen-info Ltd, Zagreb, Croatia.
181
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
182
The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
183
Public Health Sciences, Epidemiology and Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina, United States of America.
184
Cardiovascular Health Research Unit, Epidemiology, Medicine and Health Services, University of Washington, Seattle, Washington, United States of America.
185
Kaiser Permanente Washington, Health Research Institute, Seattle, Washington, United States of America.
186
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
187
Biostatistics, Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
188
Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
189
The Framingham Heart Study, Framingham, Massachusetts, United States of America.
190
Cardiology, Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
191
Fred Hutchinson Cancer Research Center, University of Washington School of Public Health, Seattle, Washington, United States of America.
192
Medicine, Columbia University Medical Center, New York, New York, United States of America.
193
The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

Abstract

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Conflict of interest statement

The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. OHF is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Terho Lehtimäki (TL) is employed by Fimlab Ltd. Ozren Polašek (OP) is employed by Gen‐info Ltd. There are no patents, products in development, or marked products to declare. All the other authors have declared no competing interests exist. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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