Genetic diversity fuels gene discovery for tobacco and alcohol use
Gretchen Saunders(University of Minnesota), Xingyan Wang(Pennsylvania State University), Fang Chen(Pennsylvania State University), Seon-Kyeong Jang(University of Minnesota), Mengzhen Liu(University of Minnesota), Chen Wang(Pennsylvania State University), Shuang Gao(Pennsylvania State University), Yu Jiang(Stanford University), Chachrit Khunsriraksakul(Pennsylvania State University), Jacqueline M. Otto(University of Minnesota), Clifton Addison(Jackson State University), Masato Akiyama(Kyushu University), Christine M. Albert(Cedars-Sinai Medical Center), Fazil Alıev(Rutgers, The State University of New Jersey), Álvaro Alonso(Emory University), Donna K. Arnett(University of Kentucky), Allison E. Ashley‐Koch(Duke University), Aneel A. Ashrani(Mayo Clinic), Kathleen C. Barnes(Tempus Labs (United States)), R. Graham Barr(Columbia University Irving Medical Center), Traci M. Bartz(University of Washington), Diane M. Becker(Johns Hopkins University), Lawrence F. Bielak(University of Michigan), Emelia J. Benjamin(Boston University), Joshua C. Bis(University of Washington), Gyða Björnsdóttir(deCODE Genetics (Iceland)), John Blangero(The University of Texas Rio Grande Valley), Eugene R. Bleecker(University of Arizona), Jason D. Boardman(University of Colorado Boulder), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Dorret I. Boomsma(Vrije Universiteit Amsterdam), Meher P. Boorgula(University of Colorado Anschutz Medical Campus), Donald W. Bowden(Wake Forest University), Jennifer A. Brody(University of Washington), Brian E. Cade(Broad Institute), Daniel I. Chasman(Brigham and Women's Hospital), Sameer Chavan(University of Colorado Anschutz Medical Campus), Yii‐Der Ida Chen(UCLA Medical Center), Zhengming Chen(University of Oxford), Iona Cheng(University of California, San Francisco), Michael H. Cho(Brigham and Women's Hospital), Hélène Choquet(Kaiser Permanente), John W. Cole(University of Maryland, Baltimore), Marilyn C. Cornelis(Northwestern University), Francesco Cucca(University of Sassari), Joanne E. Curran(The University of Texas Rio Grande Valley), Mariza de Andrade(Mayo Clinic), Danielle M. Dick(Rutgers, The State University of New Jersey), Anna R. Docherty(Huntsman (United States)), Ravindranath Duggirala(The University of Texas Rio Grande Valley), Charles B. Eaton(Brown University), Marissa A. Ehringer(University of Colorado Boulder), Tõnu Esko(University of Tartu), Jessica D. Faul(University of Michigan), Lilian Fernandes Silva(University of Eastern Finland), Edoardo Fiorillo(Institute of Genetic and Biomedical Research), Myriam Fornage(Brown Foundation), Barry I. Freedman(Wake Forest University), Maiken E. Gabrielsen(Norwegian University of Science and Technology), Melanie E. Garrett(Duke University), Sina A. Gharib(University of Washington), Christian Gieger(Helmholtz Zentrum München), Nathan A. Gillespie(Virginia Commonwealth University), David C. Glahn(Boston Children's Hospital), Scott D. Gordon(QIMR Berghofer Medical Research Institute), C. Charles Gu(Washington University in St. Louis), Dongfeng Gu(Chinese Academy of Medical Sciences & Peking Union Medical College), Daníel F. Guðbjartsson(deCODE Genetics (Iceland)), Xiuqing Guo(UCLA Medical Center), Jeffrey Haessler(Fred Hutch Cancer Center), Michael E. Hall(Jackson Memorial Hospital), Toomas Haller(University of Tartu), Kathleen Mullan Harris(University of North Carolina at Chapel Hill), Jiang He(Tulane University), Pamela Herd(Georgetown University), John K. Hewitt(University of Colorado Boulder), Ian B. Hickie(The University of Sydney), Bertha Hidalgo(University of Alabama at Birmingham), John E. Hokanson(University of Colorado Anschutz Medical Campus), Christian J. Hopfer(University of Colorado Anschutz Medical Campus), Jouke‐Jan Hottenga(Vrije Universiteit Amsterdam), Lifang Hou(Northwestern University), Hongyan Huang(Harvard University), Yi‐Jen Hung(National Defense Medical Center), David J. Hunter(University of Oxford), Kristian Hveem(Norwegian University of Science and Technology), Shih‐Jen Hwang(National Institutes of Health), Chii‐Min Hwu(Taipei Veterans General Hospital), William G. Iacono(University of Minnesota), Marguerite R. Irvin(University of Alabama at Birmingham), Yon Ho Jee(Harvard University), Eric O. Johnson(RTI International), Yoonjung Yoonie Joo(Northwestern University), Eric Jorgenson(Regeneron (United States)), Anne E. Justice(University of North Carolina at Chapel Hill), Yoichiro Kamatani(RIKEN Center for Integrative Medical Sciences), Robert C. Kaplan(Albert Einstein College of Medicine), Jaakko Kaprio(University of Helsinki), Sharon L. R. Kardia(University of Michigan), Matthew C. Keller(University of Colorado Boulder), Tanika N. Kelly(Tulane University), Charles Kooperberg(University of Washington), Tellervo Korhonen(University of Helsinki), Peter Kraft(Harvard University), Kenneth Krauter(University of Colorado Boulder), Johanna Kuusisto(University of Eastern Finland), Markku Laakso(University of Eastern Finland), Jessica Lasky‐Su(Brigham and Women's Hospital), Wen‐Jane Lee(Taichung Veterans General Hospital), James J. Lee(University of Minnesota), Daniel Levy(National Institutes of Health), Liming Li(Peking University), Kevin Li(University of Michigan), Yuqing Li(University of California, San Francisco), Kuang Lin(University of Oxford), Penelope A. Lind(Queensland University of Technology), Chunyu Liu(Boston University), Donald M. Lloyd‐Jones(Northwestern University), Sharon M. Lutz(Harvard University), Jiantao Ma(Tufts University), Reedik Mägi(University of Colorado Boulder), Ani Manichaikul(University of Virginia), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Ravi Mathur(RTI International), Nana Matoba(University of North Carolina at Chapel Hill), Patrick F. McArdle(University of Maryland, Baltimore), Matt McGue(University of Minnesota), Matthew B. McQueen(University of Colorado Boulder), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Andres Metspalu(University of Tartu), Deborah A. Meyers(University of Arizona), Iona Y. Millwood(University of Oxford), Braxton D. Mitchell(University of Maryland, Baltimore), Karen L. Mohlke(University of North Carolina at Chapel Hill), Matthew Moll(Brigham and Women's Hospital), May E. Montasser(University of Maryland, Baltimore), Alanna C. Morrison(The University of Texas Health Science Center at Houston), Antonella Mulas(Institute of Genetic and Biomedical Research), Jonas B. Nielsen(Norwegian University of Science and Technology), Kari E. North(University of North Carolina at Chapel Hill), Elizabeth C. Oelsner(Columbia University Irving Medical Center), Yukinori Okada(RIKEN Center for Integrative Medical Sciences), Valeria Orrù(Institute of Genetic and Biomedical Research), Nicholette D. Palmer(Wake Forest University), Teemu Palviainen(University of Helsinki), Anita Pandit(University of Michigan), S. Lani Park(University of Hawaiʻi at Mānoa), Ulrike Peters(University of Washington), Annette Peters(Helmholtz Zentrum München), Patricia A. Peyser(University of Michigan), Tinca J. C. Polderman(Amsterdam University Medical Centers), Nicholas Rafaels(University of Colorado Anschutz Medical Campus), Susan Redline(Brigham and Women's Hospital), Robert M. Reed(University of Maryland, Baltimore), Alex P. Reiner(University of Washington), John P. Rice(Washington University in St. Louis), Stephen S. Rich(University of Virginia), Nicole Richmond(University of Colorado Anschutz Medical Campus), Carol Roan(University of Wisconsin–Madison), Jerome I. Rotter(UCLA Medical Center), Michael Rueschman(Brigham and Women's Hospital), Valgerður Rúnarsdóttir(Society of Alcoholism and other Addictions), Nancy L. Saccone(Washington University in St. Louis), David A. Schwartz(Pulmonary and Critical Care Associates), Aladdin H. Shadyab(University of California San Diego), Jingchunzi Shi(23andMe (United States)), Suyash Shringarpure(23andMe (United States)), Kamil Sicinski(University of Wisconsin–Madison), Anne Heidi Skogholt(Norwegian University of Science and Technology), Jennifer A. Smith(University of Michigan), Nicholas L. Smith(Kaiser Permanente Washington Health Research Institute), Nona Sotoodehnia(University of Washington), Michael C. Stallings(University of Colorado Boulder), Hreinn Stefánsson(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Jerry A. Stitzel(University of Colorado Boulder), Xiao Sun(Tulane University), Moin Syed(University of Minnesota), Ruth Tal‐Singer(COPD Foundation), Amy E. Taylor(University Hospitals Bristol NHS Foundation Trust), Kent D. Taylor(UCLA Medical Center), Marilyn J. Telen(Duke University), Khanh K. Thai(Kaiser Permanente), Hemant K. Tiwari(University of Alabama at Birmingham), Constance Turman(Harvard University), Þórarinn Tyrfingsson(Society of Alcoholism and other Addictions), Tamara L. Wall(University of California San Diego), Robin Walters(University of Oxford), David R. Weir(University of Michigan), Scott T. Weiss(Brigham and Women's Hospital), Wendy White(Tougaloo College), John B. Whitfield(QIMR Berghofer Medical Research Institute), Kerri L. Wiggins(University of Washington), Gonneke Willemsen(Vrije Universiteit Amsterdam), Cristen J. Willer(University of Michigan), Bendik S. Winsvold(Oslo University Hospital), Huichun Xu(University of Maryland, Baltimore), Lisa R. Yanek(Johns Hopkins University), Jie Yin(Kaiser Permanente), Kristin L. Young(University of North Carolina at Chapel Hill), Kendra A. Young(University of North Carolina at Chapel Hill), Bing Yu(The University of Texas Health Science Center at Houston), Wei Zhao(University of Michigan), Wei Zhou(University of Michigan), Sebastian Zöllner(University of Michigan), Luisa Zuccolo(University of Bristol), The Biobank Japan Project(University of Leicester), Chiara Batini(Oregon Research Institute), Andrew W. Bergen(Oregon Research Institute), Laura J. Bierut(NorthShore University HealthSystem), Sean P. David(NorthShore University HealthSystem), Sarah A. Gagliano Taliun(RTI International), Dana B. Hancock(Pennsylvania State University), Bibo Jiang(Pennsylvania State University), Marcus R. Munafò(deCODE Genetics (Iceland)), Thorgeir E. Thorgeirsson(Pennsylvania State University), Dajiang J. Liu(University of Minnesota), Scott Vrieze(University of Minnesota)
Cited by 504Open Access
Abstract
Abstract Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury 1–4 . These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries 5 . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
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