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Am J Hum Genet. 2018 Mar 1;102(3):375-400. doi: 10.1016/j.ajhg.2018.01.015. Epub 2018 Feb 15.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Sung YJ1, Winkler TW2, de Las Fuentes L3, Bentley AR4, Brown MR5, Kraja AT6, Schwander K7, Ntalla I8, Guo X9, Franceschini N10, Lu Y11, Cheng CY12, Sim X13, Vojinovic D14, Marten J15, Musani SK16, Li C17, Feitosa MF6, Kilpeläinen TO18, Richard MA19, Noordam R20, Aslibekyan S21, Aschard H22, Bartz TM23, Dorajoo R24, Liu Y25, Manning AK26, Rankinen T27, Smith AV28, Tajuddin SM29, Tayo BO30, Warren HR31, Zhao W32, Zhou Y33, Matoba N34, Sofer T35, Alver M36, Amini M37, Boissel M38, Chai JF39, Chen X40, Divers J25, Gandin I41, Gao C42, Giulianini F43, Goel A44, Harris SE45, Hartwig FP46, Horimoto ARVR47, Hsu FC25, Jackson AU48, Kähönen M49, Kasturiratne A50, Kühnel B51, Leander K52, Lee WJ53, Lin KH54, 'an Luan J55, McKenzie CA56, Meian H57, Nelson CP58, Rauramaa R59, Schupf N60, Scott RA55, Sheu WHH61, Stančáková A62, Takeuchi F63, van der Most PJ37, Varga TV64, Wang H65, Wang Y65, Ware EB66, Weiss S67, Wen W68, Yanek LR69, Zhang W70, Zhao JH55, Afaq S71, Alfred T11, Amin N14, Arking D72, Aung T12, Barr RG73, Bielak LF32, Boerwinkle E74, Bottinger EP11, Braund PS58, Brody JA75, Broeckel U76, Cabrera CP31, Cade B77, Caizheng Y57, Campbell A78, Canouil M38, Chakravarti A79; CHARGE Neurology Working Group, Chauhan G80, Christensen K81, Cocca M41; COGENT-Kidney Consortium, Collins FS82, Connell JM83, de Mutsert R84, de Silva HJ85, Debette S86, Dörr M87, Duan Q88, Eaton CB89, Ehret G90, Evangelou E91, Faul JD92, Fisher VA33, Forouhi NG55, Franco OH14, Friedlander Y93, Gao H94; GIANT Consortium, Gigante B52, Graff M10, Gu CC7, Gu D95, Gupta P96, Hagenaars SP97, Harris TB98, He J99, Heikkinen S100, Heng CK101, Hirata M102, Hofman A14, Howard BV103, Hunt S104, Irvin MR21, Jia Y9, Joehanes R105, Justice AE10, Katsuya T106, Kaufman J107, Kerrison ND55, Khor CC108, Koh WP109, Koistinen HA110, Komulainen P59, Kooperberg C111, Krieger JE47, Kubo M112, Kuusisto J113, Langefeld CD25, Langenberg C55, Launer LJ98, Lehne B71, Lewis CE114, Li Y7; Lifelines Cohort Study115, Lim SH96, Lin S6, Liu CT33, Liu J116, Liu J117, Liu K118, Liu Y9, Loh M119, Lohman KK25, Long J68, Louie T35, Mägi R36, Mahajan A120, Meitinger T121, Metspalu A36, Milani L36, Momozawa Y122, Morris AP123, Mosley TH Jr124, Munson P125, Murray AD126, Nalls MA127, Nasri U9, Norris JM128, North K10, Ogunniyi A129, Padmanabhan S130, Palmas WR131, Palmer ND132, Pankow JS133, Pedersen NL40, Peters A134, Peyser PA32, Polasek O135, Raitakari OT136, Renström F137, Rice TK7, Ridker PM43, Robino A138, Robinson JG139, Rose LM43, Rudan I140, Sabanayagam C141, Salako BL129, Sandow K9, Schmidt CO142, Schreiner PJ133, Scott WR143, Seshadri S144, Sever P145, Sitlani CM75, Smith JA32, Snieder H37, Starr JM146, Strauch K147, Tang H148, Taylor KD9, Teo YY149, Tham YC96, Uitterlinden AG150, Waldenberger M51, Wang L6, Wang YX151, Wei WB152, Williams C6, Wilson G153, Wojczynski MK6, Yao J9, Yuan JM154, Zonderman AB155, Becker DM69, Boehnke M48, Bowden DW132, Chambers JC70, Chen YI9, de Faire U52, Deary IJ97, Esko T156, Farrall M44, Forrester T56, Franks PW157, Freedman BI158, Froguel P159, Gasparini P160, Gieger C161, Horta BL46, Hung YJ162, Jonas JB163, Kato N63, Kooner JS164, Laakso M113, Lehtimäki T165, Liang KW166, Magnusson PKE40, Newman AB167, Oldehinkel AJ168, Pereira AC169, Redline S77, Rettig R170, Samani NJ58, Scott J171, Shu XO68, van der Harst P172, Wagenknecht LE173, Wareham NJ55, Watkins H44, Weir DR92, Wickremasinghe AR50, Wu T57, Zheng W68, Kamatani Y34, Laurie CC35, Bouchard C27, Cooper RS30, Evans MK29, Gudnason V28, Kardia SLR32, Kritchevsky SB174, Levy D175, O'Connell JR176, Psaty BM177, van Dam RM178, Sims M16, Arnett DK179, Mook-Kanamori DO180, Kelly TN181, Fox ER182, Hayward C15, Fornage M19, Rotimi CN4, Province MA6, van Duijn CM14, Tai ES183, Wong TY12, Loos RJF184, Reiner AP111, Rotter JI185, Zhu X65, Bierut LJ186, Gauderman WJ187, Caulfield MJ31, Elliott P94, Rice K35, Munroe PB188, Morrison AC5, Cupples LA189, Rao DC7, Chasman DI190.

Author information

1
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: yunju@wustl.edu.
2
Department of Genetic Epidemiology, University of Regensburg, Regensburg 93051, Germany.
3
Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO 63110, USA.
4
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
5
Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas School of Public Health, Houston, TX 77030, USA.
6
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA.
7
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA.
8
William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK.
9
Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
10
Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC 27514, USA.
11
Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY 10029, USA.
12
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore 169857, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 117597, Singapore.
13
Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore.
14
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
15
Medical Research Council Human Genetics Unit, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
16
Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39213, USA.
17
Department of Epidemiology and Biostatistics, University of Giorgia at Athens College of Public Health, Athens, GA 30602, USA.
18
Section of Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark; Department of Environmental Medicine and Public Health, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
19
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
20
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
21
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
22
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Centre de Bioinformatique Biostatistique et Biologie Integrative (C3BI), Institut Pasteur, Paris 75015, France.
23
Cardiovascular Health Research Unit, Biostatistics and Medicine, University of Washington, Seattle, WA 98101, USA.
24
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore.
25
Division of Biostatistical Sciences, Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
26
Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
27
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
28
Icelandic Heart Association, Kopavogur 201, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
29
Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
30
Department of Public Health Sciences, Loyola University Chicago, Maywood, IL 60153, USA.
31
William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
32
School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA.
33
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
34
Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
35
Department of Biostatistics, University of Washington, Seattle, WA 98105, USA.
36
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
37
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
38
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille 59000, France.
39
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore.
40
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
41
Department of Medical Sciences, University of Trieste, Trieste 34137, Italy.
42
Department of Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
43
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
44
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
45
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh EH4 2XU, UK.
46
Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, RS 96020220, Brazil.
47
Lab Genetics and Molecular Cardiology, Department of Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil.
48
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
49
Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland; Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
50
Department of Public Health, University of Kelaniya, Ragama, Sri Lanka.
51
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
52
Institute of Environmental Medicine, Karolinska Institutet, Stockholm 17177, Sweden.
53
Department of Medical Research, Taichung Veterans General Hospital, Department of Social Work, Tunghai University, Taichung 40705, Taiwan.
54
Department of Opthalmology, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
55
MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
56
Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona JMAAW15, Jamaica.
57
Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Tongji Medical College Huazhong University of Science and Technology, Wuhan, China.
58
Department of Cardiovascular Sciences, University of Leicester, Leicester LE3 9QP, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
59
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio 70100, Finland.
60
Taub Institute for Research on Alzheimer disease and the Aging Brain, Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
61
Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; School of Medicine, National Yang-ming University, Taipei, Taiwan; School of Medicine, National Defense Medical Center, Taipei, Taiwan; Institute of Medical Technology, National Chung-Hsing University, Taichung 40705, Taiwan.
62
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio 70210, Finland.
63
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo 1628655, Japan.
64
Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Skåne 205 02, Sweden.
65
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
66
School of Public Health, Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA; Institute for Social Research, Research Center for Group Dynamics, University of Michigan, Ann Arbor, MI 48104, USA.
67
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz Arndt University Greifswald, Greifswald 17487, Germany; DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany.
68
Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
69
General Internal Medicine, GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
70
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK.
71
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK.
72
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
73
Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, NY 10032, USA.
74
Human Genetics Center, The University of Texas School of Public Health, Houston, TX 77030, USA; Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX 77030, USA.
75
Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, WA 98101, USA.
76
Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
77
Sleep Medicine and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA.
78
Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
79
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
80
Centre for Brain Research, Indian Institute of Schience, Bangalore 560012, India.
81
The Danish Aging Research Center, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
82
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
83
Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
84
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
85
Department of Medicine, University of Kelaniya, Ragama, Sri Lanka.
86
Inserm U1219 Neuroepidemiology, University of Bordeaux, Bordeaux, France; Department of Neurology, University Hospital, Bordeaux, France; Boston University School of Medicine, Boston, MA 02118, USA.
87
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany; Department of Internal Medicine B, University Medicine Greifswald, Greifswald 17475, Germany.
88
Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA.
89
Department of Family Medicine and Epidemiology, Alpert Medical School of Brown University, Providence, RI 02860, USA.
90
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Division of Cardiology, Department of Specialties of Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
91
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina 45110, Greece.
92
Institute for Social Research, Survey Research Center, University of Michigan, Ann Arbor, MI 48104, USA.
93
Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem 91120, Israel.
94
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; MRC-PHE Centre for Environment and Health, Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, UK.
95
Department of Epidemiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
96
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore.
97
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Department of Psychology, The University of Edinburgh, Edinburgh EH8 9JZ, UK.
98
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
99
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
100
University of Eastern Finland, Institute of Biomedicine, Kuopio 70211, Finland.
101
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Khoo Teck Puat - National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore.
102
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku 108-8639, Japan.
103
MedStar Health Research Institute, Hyattsville, MD 20782, USA; Center for Clinical and Translational Sciences and Department of Medicine, Georgetown-Howard Universities, Washington, DC 20057, USA.
104
Cardiovascular Genetics, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84108, USA; Weill Cornell Medicine in Qatar, Doha, Qatar.
105
Hebrew SeniorLife, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02131, USA; Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA.
106
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita 5650871, Japan; Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita 5650871, Japan.
107
Epidemiology, Department of Occupational and Environmental Medicine Program, University of Washington, Seattle, WA 98105, USA.
108
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore.
109
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore.
110
Department of Health, National Institute for Health and Welfare, Helsinki 00271, Finland; Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029, Finland.
111
Fred Hutchinson Cancer Research Center, University of Washington School of Public Health, Seattle, WA 98109, USA.
112
Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
113
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
114
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35205, USA.
115
Lifelines cohort study, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
116
Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore; Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore.
117
WHI CCC, Fred Hutchinson Cancer Research Center, Seattle, WA 98115, USA.
118
Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
119
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research 138648, Singapore.
120
Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
121
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Institute of Human Genetics, Technische Universität München, Munich 80333, Germany.
122
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
123
Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
124
Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
125
Mathematical and Statistical Computing Laboratory, Center for Information Technology, NIH, Bethesda, MD 20892, USA.
126
The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen AB25 2ZD, UK.
127
Data Tecnica International, Glen Echo, MD 20812, USA; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA.
128
Department of Epidemiology, Colorado School of Public Health, Aurora, CO 80045, USA.
129
Department of Medicine, University of Ibadan, Ibadan, Nigeria.
130
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
131
Internal Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
132
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
133
Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55454, USA.
134
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Neuherberg 85764, Germany.
135
Faculty of Medicine, University of Split, Split, Croatia.
136
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
137
Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Skåne 205 02, Sweden; Department of Biobank Research, Umeå University, Umeå, Västerbotten 901 87, Sweden.
138
Medical Genetics, IRCCS Burlo, Garofolo 34137, Italy.
139
Department of Epidemiology and Medicine, University of Iowa, Iowa City, IA 52242, USA.
140
Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, UK.
141
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore 169856, Singapore; Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore 169857, Singapore.
142
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany; Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
143
Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK; National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
144
Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
145
International Centre for Circulatory Health, Imperial College London, London W2 1PG, UK.
146
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh EH8 9JZ, UK.
147
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich 81377, Germany.
148
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
149
Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore; Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore 117456, Singapore; NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117456, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore.
150
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
151
Beijing Institute of Ophthalmology, Beijing Ophthalmology and Visual Science Key Lab, Beijing Tongren Eye Center, Capital Medical University, Beijing, China 100730, China.
152
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
153
Jackson Heart Study, Department of Public Health, Jackson State University, Jackson, MS 39213, USA.
154
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA; Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
155
Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
156
Estonian Genome Center, University of Tartu, Tartu 51010, Estonia; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA.
157
Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Malmö, Skåne 205 02, Sweden; Harvard T.H. Chan School of Public Health, Department of Nutrition, Harvard University, Boston, MA 02115, USA; Department of Public Health & Clinical Medicine, Umeå University, Umeå, Västerbotten 901 85, Sweden.
158
Division of Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
159
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, Lille 59000, France; Department of Genomics of Common Disease, Imperial College London, London W12 0NN, UK.
160
Department of Medical Sciences, University of Trieste, Trieste 34137, Italy; Division Experimental Genetics, Sidra, Doha 26999, Qatar.
161
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg 85764, Germany.
162
Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taipei 11490, Taiwan.
163
Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; Department of Ophthalmology, Medical Faculty Mannheim, University Heidelberg, Mannheim 68167, Germany.
164
Department of Cardiology, Ealing Hospital, Middlesex UB1 3HW, UK; National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
165
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Lifes Sciences, University of Tampere, Tampere 33014, Finland.
166
School of Medicine, National Yang-ming University, Taipei, Taiwan; Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan; Department of Medicine, China Medical University, Taichung 40705, Taiwan.
167
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
168
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
169
Lab Genetics and Molecular Cardiology, Department of Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo, Brazil; Genetics, Harvard Medical School, Boston, MA 02115, USA.
170
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany; Institute of Physiology, University Medicine Greifswald, Greifswald 17495, Germany.
171
National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
172
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
173
Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
174
Sticht Center for Health Aging and Alzheimer's Prevention, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
175
Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
176
Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
177
Cardiovascular Health Research Unit, Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington, Health Research Institute, Seattle, WA 98101, USA.
178
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
179
Dean's Office, University of Kentucky College of Public Health, Lexington, KY 40536, USA.
180
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2300RC, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
181
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
182
Cardiology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
183
Saw Swee Hock School of Public Health, National University Health System and National University of Singapore, Singapore, Singapore 117549, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
184
Icahn School of Medicine at Mount Sinai, The Charles Bronfman Institute for Personalized Medicine, New York, NY 10029, USA; Icahn School of Medicine at Mount Sinai, The Mindich Child Health and Development Institute, New York, NY 10029, USA.
185
Genomic Outcomes, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA; Genomic Outcomes, Department of Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
186
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
187
Division of Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90032, USA.
188
William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London EC1M 6BQ, UK.
189
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; Framingham Heart Study, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20982, USA.
190
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: dchasman@research.bwh.harvard.edu.

Abstract

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

KEYWORDS:

GWAS; GxE interactions; blood pressure; lifestyle; multi-ancestry; smoking

PMID:
29455858
PMCID:
PMC5985266
DOI:
10.1016/j.ajhg.2018.01.015
[Indexed for MEDLINE]
Free PMC Article

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