Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
Mary F. Feitosa(Washington University in St. Louis), Aldi T. Kraja(Washington University in St. Louis), Daniel I. Chasman(Brigham and Women's Hospital), Yun J. Sung(Washington University in St. Louis), Thomas W. Winkler(University of Regensburg), Ιωάννα Ντάλλα(Queen Mary University of London), Xiuqing Guo(The Lundquist Institute), Nora Franceschini(University of North Carolina at Chapel Hill), Ching‐Yu Cheng(National University of Singapore), Xueling Sim(National University of Singapore), Dina Vojinović(Erasmus MC), Jonathan Marten(Institute of Genetics and Cancer), Solomon K. Musani(Jackson Memorial Hospital), Changwei Li(University of Georgia), Amy R. Bentley(National Institutes of Health), Michael R. Brown(Queen Mary University of London), Karen Schwander(Washington University in St. Louis), Melissa A. Richard(Brown Foundation), Raymond Noordam(Leiden University Medical Center), Hugues Aschard(Harvard University), Traci M. Bartz(University of Washington), Lawrence F. Bielak(University of Michigan), Rajkumar Dorajoo(Agency for Science, Technology and Research), Virginia Fisher(Boston University), Fernando Pires Hartwig(Universidade Federal de Pelotas), A.R.V.R. Horimoto(Universidade de São Paulo), Kurt K. Lohman(Wake Forest University), Alisa K. Manning(Harvard University), Tuomo Rankinen(Pennington Biomedical Research Center), Albert V. Smith(University of Iceland), Salman M. Tajuddin(National Institutes of Health), Mary K. Wojczynski(Washington University in St. Louis), Maris Alver(University of Tartu), Mathilde Boissel(Centre National de la Recherche Scientifique), Qiuyin Cai(Vanderbilt University), Archie Campbell(Edinburgh Cancer Research), Jin Fang Chai(National University of Singapore), Xu Chen(Karolinska Institutet), Jasmin Divers(Wake Forest University), Chuan Gao(Wake Forest University), Anuj Goel(Centre for Human Genetics), Yanick Hagemeijer(University Medical Center Groningen), Sarah E. Harris(Institute of Genetics and Cancer), Meian He(Huazhong University of Science and Technology), Fang‐Chi Hsu(Wake Forest University), Anne Jackson(University of Michigan), Mika Kähönen(Tampere University), Anuradhani Kasturiratne(University of Kelaniya), Pirjo Komulainen, Brigitte Kühnel(Helmholtz Zentrum München), Federica Laguzzi(Karolinska Institutet), Jian’an Luan(University of Cambridge), Nana Matoba(RIKEN Center for Integrative Medical Sciences), Ilja M. Nolte(University Medical Center Groningen), Sandosh Padmanabhan(University of Glasgow), Muhammad Riaz(University of Leicester), Rico Rueedi(SIB Swiss Institute of Bioinformatics), Antonietta Robino(IRCCS Materno Infantile Burlo Garofolo), M. Abdullah Said(University Medical Center Groningen), Robert A. Scott(University of Cambridge), Tamar Sofer(Brigham and Women's Hospital), Alena Stančáková(University of Eastern Finland), Fumihiko Takeuchi(National Center for Global Health and Medicine), Bamidele O. Tayo(Loyola University Chicago), Peter J. van der Most(University Medical Center Groningen), Tibor V. Varga(Lund University), Véronique Vitart(Institute of Genetics and Cancer), Yajuan Wang(Beijing Tongren Hospital), Erin B. Ware(University of Michigan), Helen Warren(Queen Mary University of London), Stefan Weiß(Universität Greifswald), Wanqing Wen(Vanderbilt University), Lisa R. Yanek(Johns Hopkins University), Weihua Zhang(Ealing Hospital), Jing Hua Zhao(University of Cambridge), Saima Afaq(Imperial College London), Najaf Amin(Erasmus MC), Marzyeh Amini(University Medical Center Groningen), Dan E. Arking(Johns Hopkins University), Tin Aung(National University of Singapore), Eric Boerwinkle(Baylor College of Medicine), Ingrid B. Borecki(Washington University in St. Louis), Ulrich Broeckel(Medical College of Wisconsin), Morris J. Brown(Queen Mary University of London), Marco Brumat(University of Trieste), Gregory L. Burke(Wake Forest University), Mickaël Canouil(Centre National de la Recherche Scientifique), Aravinda Chakravarti(Johns Hopkins University), Charumathi Sabanayagam(Singapore National Eye Center), Yii-Der Ida Chen(The Lundquist Institute), John Connell(University of Dundee), Adolfo Correa(Jackson Memorial Hospital), Lisa de las Fuentes(Washington University in St. Louis), Renée de Mutsert(Leiden University Medical Center), H. Janaka de Silva(University of Kelaniya), Xuan Deng(Boston University), Jingzhong Ding(Wake Forest University), Qing Duan(University of North Carolina at Chapel Hill), Charles B. Eaton(Brown University), Georg Ehret(University Hospital of Geneva), Ruben N. Eppinga(University Medical Center Groningen), Εvangelos Εvangelou(University of Ioannina), Jessica D. Faul(University of Michigan), Stephan B. Felix(Universitätsmedizin Greifswald), Nita G. Forouhi(University of Cambridge), Terrence Forrester(University of the West Indies), Oscar H. Franco(Erasmus MC), Yechiel Friedlander(Hadassah Medical Center), Ilaria Gandin(University of Trieste), He Gao(Imperial College London), Mohsen Ghanbari(Mashhad University of Medical Sciences), Bruna Gigante(Karolinska Institutet), C. Charles Gu(Washington University in St. Louis), Dongfeng Gu(Chinese Academy of Medical Sciences & Peking Union Medical College), Saskia P. Hagenaars(University of Edinburgh), Göran Hallmans(Umeå University), Tamara B. Harris(National Institutes of Health), Jiang He(Tulane University), Sami Heikkinen(University of Eastern Finland), Chew‐Kiat Heng(National University of Singapore), Makoto Hirata(The University of Tokyo), Barbara V. Howard(Georgetown-Howard Universities Center for Clinical and Translational Science), M. Arfan Ikram(Erasmus MC), Ulrich John(Universitätsmedizin Greifswald), Tomohiro Katsuya(The University of Osaka), Chiea Chuen Khor(Agency for Science, Technology and Research), Tuomas O. Kilpeläinen(University of Copenhagen), Woon‐Puay Koh(National University of Singapore), José Eduardo Krieger(Universidade de São Paulo), Stephen B. Kritchevsky(Wake Forest University), Michiaki Kubo(RIKEN Center for Integrative Medical Sciences), Johanna Kuusisto(University of Eastern Finland), Timo A. Lakka(University of Eastern Finland), Carl D. Langefeld(Wake Forest University), Claudia Langenberg(University of Cambridge), Lenore J. Launer(National Institutes of Health), Benjamin Lehne(Imperial College London), Cora E. Lewis(University of Alabama at Birmingham), Yize Li(Washington University in St. Louis), Shiow J. Lin(Washington University in St. Louis), Jianjun Liu(Agency for Science, Technology and Research), Jingmin Liu(Agency for Science, Technology and Research), Marie Loh(Agency for Science, Technology and Research), Tin Louie(University of Washington), Reedik Mägi(University of Tartu), Colin A. McKenzie(University of the West Indies), Thomas Meitinger(Helmholtz Zentrum München), Andres Metspalu(University of Tartu), Yuri Milaneschi(Amsterdam Neuroscience), Lili Milani(University of Tartu), Karen L. Mohlke(University of North Carolina at Chapel Hill), Yukihide Momozawa(RIKEN Center for Integrative Medical Sciences), Mike A. Nalls(Data Tecnica International (United States)), Christopher P. Nelson(University of Leicester), Nona Sotoodehnia(University of Washington), Jill M. Norris(Colorado School of Public Health), Jeff O’Connell(University of Maryland, Baltimore), Nicholette D. Palmer(Wake Forest University), Thomas T. Perls(Boston University), Nancy L. Pedersen(Karolinska Institutet), Annette Peters(Helmholtz Zentrum München), Patricia A. Peyser(University of Michigan), Neil R Poulter(Imperial College London), Leslie J. Raffel(University of California, Irvine), Olli T. Raitakari(University of Turku), Kathryn Roll(The Lundquist Institute), Lynda M. Rose(Brigham and Women's Hospital), Frits R. Rosendaal(Leiden University Medical Center), Jerome I. Rotter(The Lundquist Institute), Carsten Oliver Schmidt(Universitätsmedizin Greifswald), Pamela J. Schreiner(University of Minnesota), Nicole Schupf(Columbia University Irving Medical Center), William R. Scott(Imperial College London), Peter S. Sever(Imperial College London), Yuan Shi(Singapore National Eye Center), Stephen Sidney(Kaiser Permanente), Mario Sims(Jackson Memorial Hospital), Colleen M. Sitlani(University of Washington), Jennifer A. Smith(University of Michigan), Harold Snieder(University Medical Center Groningen), John M. Starr(Alzheimer Scotland), Konstantin Strauch(Helmholtz Zentrum München), Heather M. Stringham(University of Michigan), Nicholas Tan(Singapore National Eye Center), Hua Tang(Stanford University), Kent D. Taylor(The Lundquist Institute), Yik Ying Teo(Agency for Science, Technology and Research), Yih Chung Tham(Singapore National Eye Center), Stephen T. Turner(Mayo Clinic), André G. Uitterlinden(Erasmus MC), Péter Vollenweider(University of Lausanne), Mélanie Waldenberger(Helmholtz Zentrum München), Lihua Wang(Washington University in St. Louis), Ya Xing Wang(Beijing Tongren Hospital), Wen Bin Wei(Beijing Tongren Hospital), Christine A. Williams(Washington University in St. Louis), Jie Yao(The Lundquist Institute), Caizheng Yu(Huazhong University of Science and Technology), Jian‐Min Yuan(University of Pittsburgh), Wei Zhao(University of Michigan), Alan B. Zonderman(National Institutes of Health), Diane M. Becker(Johns Hopkins University), Michael Boehnke(University of Michigan), Donald W. Bowden(Wake Forest University), John C. Chambers(Imperial College Healthcare NHS Trust), Ian J. Deary(University of Edinburgh), Tõnu Esko(Broad Institute), Martin Farrall(Centre for Human Genetics), Paul W. Franks(Harvard University), Barry I. Freedman(Wake Forest University), Philippe Froguel(Centre National de la Recherche Scientifique), Paolo Gasparini(University of Trieste), Christian Gieger(Helmholtz Zentrum München), Jost B. Jonas(Beijing Tongren Hospital), Yoichiro Kamatani(RIKEN Center for Integrative Medical Sciences), Norihiro Kato(National Center for Global Health and Medicine), Jaspal S. Kooner(Imperial College Healthcare NHS Trust), Zoltán Kutalik(SIB Swiss Institute of Bioinformatics), Markku Laakso(University of Eastern Finland), Cathy C. Laurie(University of Washington), Karin Leander(Karolinska Institutet), Terho Lehtimäki(Tampere University), Lifelines Cohort Study, Patrik K. E. Magnusson(Karolinska Institutet), Albertine J. Oldehinkel(University Medical Center Groningen), Brenda W.J.H. Penninx(Amsterdam Neuroscience), Ozren Polašek(Psychiatric Hospital Sveti Ivan), David J. Porteous(Edinburgh Cancer Research), Rainer Rauramaa, Nilesh J. Samani(University of Leicester), James Scott(Imperial College London), Xiao‐Ou Shu(Vanderbilt University), Pim van der Harst(University Medical Center Groningen), Lynne E. Wagenknecht(Wake Forest University), Nicholas J. Wareham(University of Cambridge), Hugh Watkins(Centre for Human Genetics), David R. Weir(University of Michigan), Ananda R. Wickremasinghe(University of Kelaniya), Tangchun Wu(Huazhong University of Science and Technology), Wei Zheng(Vanderbilt University), Claude Bouchard(Pennington Biomedical Research Center), Kaare Christensen(University of Southern Denmark), Michele K. Evans(National Institutes of Health), Vilmundur Guðnason(University of Iceland), Bernardo Lessa Horta(Universidade Federal de Pelotas), Sharon L. R. Kardia(University of Michigan), Ching‐Ti Liu(Wake Forest University), Alexandre C. Pereira(Universidade de São Paulo), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), Paul M. Ridker(Brigham and Women's Hospital), Rob M. van Dam(National University of Singapore), W. James Gauderman(University of Southern California), Xiaofeng Zhu(Case Western Reserve University), Dennis O. Mook‐Kanamori(Leiden University Medical Center), Myriam Fornage(Brown Foundation), Charles N. Rotimi(National Institutes of Health), L. Adrienne Cupples(Boston University), Tanika N. Kelly(Tulane University), Ervin R. Fox(University of Mississippi Medical Center), Caroline Hayward(Institute of Genetics and Cancer), Cornelia M. van Duijn(Erasmus MC), E Shyong Tai(National University of Singapore), Tien Yin Wong(National University of Singapore), Charles Kooperberg(University of Washington), Walter Palmas(Columbia University Irving Medical Center), Kenneth Rice(University of Washington), Alanna C. Morrison(The University of Texas Health Science Center at Houston), Paul Elliott(Imperial College London), Mark J. Caulfield(Queen Mary University of London), Patricia B. Munroe(Queen Mary University of London), D. C. Rao(Washington University in St. Louis), Michael A. Province(Washington University in St. Louis), Daniel Levy(National Institutes of Health)
Cited by 1,170Open Access
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.
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