Genetic diversity fuels gene discovery for tobacco and alcohol use

Gretchen R. B. Saunders, Xingyan Wang, Fang Chen, Seon-Kyeong Jang, Mengzhen Liu, Chen Wang, Shuang Gao, Yu Jiang, Chachrit Khunsriraksakul, Jacqueline M. Otto, Clifton Addison, Masato Akiyama, Christine M. Albert, Fazil Aliev, Alvaro Alonso, Donna K. Arnett, Allison E. Ashley-Koch, Aneel A. Ashrani, Kathleen C. Barnes, R. Graham Barr, Traci M. Bartz, Diane M. Becker, Lawrence F. Bielak, Emelia J. Benjamin, Joshua C. Bis, Gyda Bjornsdottir, John Blangero, Eugene R. Bleecker, Jason D. Boardman, Eric Boerwinkle, Dorret I. Boomsma, Meher Preethi Boorgula, Donald W. Bowden, Jennifer A. Brody, Brian E. Cade, Daniel I. Chasman, Sameer Chavan, Yii- Der Ida Chen, Zhengming Chen, Iona Cheng, Michael H. Cho, Hélène Choquet, John W. Cole, Marilyn C. Cornelis, Francesco Cucca, Joanne E. Curran, Mariza Andrade, Danielle M. Dick, Anna R. Docherty, Ravindranath Duggirala, Charles B. Eaton, Marissa A. Ehringer, Tõnu Esko, Jessica D. Faul, Lilian Fernandes Silva, Edoardo Fiorillo, Myriam Fornage, Barry I. Freedman, Maiken E. Gabrielsen, Melanie E. Garrett, Sina A. Gharib, Christian Gieger, Nathan Gillespie, David C. Glahn, Scott D. Gordon, Charles C. Gu, Dongfeng Gu, Daniel F. Gudbjartsson, Xiuqing Guo, Jeffrey Haessler, Michael E. Hall, Toomas Haller, Kathleen Mullan Harris, Jiang He, Pamela Herd, John K. Hewitt, Ian Hickie, Bertha Hidalgo, John E. Hokanson, Christian Hopfer, JoukeJan Hottenga, Lifang Hou, Hongyan Huang, Yi-Jen Hung, David J. Hunter, Kristian Hveem, Shih-Jen Hwang, Chii-Min Hwu, William Iacono, Marguerite R. Irvin, Yon Ho Jee, Eric O. Johnson, Yoonjung Y. Joo, Eric Jorgenson, Anne E. Justice, Yoichiro Kamatani, Robert C. Kaplan, Jaakko Kaprio, Sharon L. R. Kardia, Matthew C. Keller, Tanika N. Kelly, Charles Kooperberg, Tellervo Korhonen, Peter Kraft, Kenneth Krauter, Johanna Kuusisto, Markku Laakso, Jessica Lasky-Su, Wen-Jane Lee, James J. Lee, Daniel Levy, Liming Li, Kevin Li, Yuqing Li, Kuang Lin, Penelope A. Lind, Chunyu Liu, Donald M. Lloyd-Jones, Sharon M. Lutz, Jiantao Ma, Reedik Mägi, Ani Manichaikul, Nicholas G. Martin, Ravi Mathur, Nana Matoba, Patrick F. McArdle, Matt McGue, Matthew B. McQueen, Sarah E. Medland, Andres Metspalu, Deborah A. Meyers, Iona Y. Millwood, Braxton D. Mitchell, Karen L. Mohlke, Matthew Moll, May E. Montasser, Alanna C. Morrison, Antonella Mulas, Jonas B. Nielsen, Kari E. North, Elizabeth C. Oelsner, Yukinori Okada, Valeria Orrù, Nicholette D. Palmer, Teemu Palviainen, Anita Pandit, S. Lani Park, Ulrike Peters, Annette Peters, Patricia A. Peyser, Tinca J. C. Polderman, Nicholas Rafaels, Susan Redline, Robert M. Reed, Alex P. Reiner, John P. Rice, Stephen S. Rich, Nicole E. Richmond, Carol Roan, Jerome I. Rotter, Michael N. Rueschman, Valgerdur Runarsdottir, Nancy L. Saccone, David A. Schwartz, Aladdin H. Shadyab, Jingchunzi Shi, Suyash S. Shringarpure, Kamil Sicinski, Anne Heidi Skogholt, Jennifer A. Smith, Nicholas L. Smith, Nona Sotoodehnia, Michael C. Stallings, Hreinn Stefansson, Kari Stefansson, Jerry A. Stitzel, Xiao Sun, Moin Syed, Ruth Tal-Singer, Amy E. Taylor, Kent D. Taylor, Marilyn J. Telen, Khanh K. Thai, Hemant Tiwari, Constance Turman, Thorarinn Tyrfingsson, Tamara L. Wall, Robin G. Walters, David R. Weir, Scott T. Weiss, Wendy B. White, John B. Whitfield, Kerri L. Wiggins, Gonneke Willemsen, Cristen J. Willer, Bendik S. Winsvold, Huichun Xu, Lisa R. Yanek, Jie Yin, Kristin L. Young, Kendra A. Young, Bing Yu, Wei Zhao, Wei Zhou, Sebastian Zöllner, Luisa Zuccolo, Chiara Batini, Andrew W. Bergen, Laura J. Bierut, Sean P. David, Sarah A. Gagliano Taliun, Dana B. Hancock, Bibo Jiang, Marcus R. Munafò, Thorgeir E. Thorgeirsson, Dajiang J. Liu () and Scott Vrieze ()
Additional contact information
Gretchen R. B. Saunders: University of Minnesota
Xingyan Wang: Penn State College of Medicine
Fang Chen: Penn State College of Medicine
Seon-Kyeong Jang: University of Minnesota
Mengzhen Liu: University of Minnesota
Chen Wang: Penn State College of Medicine
Shuang Gao: Penn State College of Medicine
Yu Jiang: Department of Epidemiology & Population Health at Stanford University
Chachrit Khunsriraksakul: Penn State College of Medicine
Jacqueline M. Otto: University of Minnesota
Clifton Addison: Jackson State University
Masato Akiyama: RIKEN Center for Integrative Medical Sciences
Christine M. Albert: Cedars-Sinai Medical Center
Fazil Aliev: Rutgers Robert Wood Johnson Medical School
Alvaro Alonso: Emory University
Donna K. Arnett: College of Public Health, University of Kentucky
Allison E. Ashley-Koch: Duke University School of Medicine
Aneel A. Ashrani: Mayo Clinic College of Medicine and Science
Kathleen C. Barnes: University of Colorado Anschutz Medical Campus
R. Graham Barr: Columbia University Medical Center
Traci M. Bartz: University of Washington
Diane M. Becker: Johns Hopkins University School of Medicine
Lawrence F. Bielak: University of Michigan
Emelia J. Benjamin: Boston University School of Medicine
Joshua C. Bis: University of Washington
Gyda Bjornsdottir: deCODE Genetics/Amgen, Inc.
John Blangero: University of Texas Rio Grande Valley School of Medicine
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 Preethi Boorgula: University of Colorado Anschutz Medical Campus
Donald W. Bowden: Wake Forest School of Medicine
Jennifer A. Brody: University of Washington
Brian E. Cade: Brigham and Women’s Hospital
Daniel I. Chasman: Brigham and Women’s Hospital and Harvard Medical School
Sameer Chavan: University of Colorado Anschutz Medical Campus
Yii- Der Ida Chen: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Zhengming Chen: University of Oxford
Iona Cheng: University of California
Michael H. Cho: Brigham and Women’s Hospital
Hélène Choquet: Division of Research
John W. Cole: Baltimore Veterans Affairs Medical Center
Marilyn C. Cornelis: Northwestern University Feinberg School of Medicine
Francesco Cucca: University of Sassari
Joanne E. Curran: University of Texas Rio Grande Valley School of Medicine
Mariza Andrade: Mayo Clinic College of Medicine and Science
Danielle M. Dick: Rutgers Robert Wood Johnson Medical School
Anna R. Docherty: University of Utah School of Medicine
Ravindranath Duggirala: University of Texas Rio Grande Valley School of Medicine
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: Consiglio Nazionale delle Ricerche (CNR)
Myriam Fornage: The University of Texas Health Science Center at Houston
Barry I. Freedman: Wake Forest School of Medicine
Maiken E. Gabrielsen: Norwegian University of Science and Technology
Melanie E. Garrett: Duke University School of Medicine
Sina A. Gharib: University of Washington
Christian Gieger: German Research Center for Environmental Health
Nathan Gillespie: Virginia Commonwealth University
David C. Glahn: Boston Children’s Hospital & Harvard Medical School
Scott D. Gordon: QIMR Berghofer Medical Research Institute
Charles C. Gu: Washington University School of Medicine
Dongfeng Gu: Chinese Academy of Medical Sciences and Peking Union Medical College
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Xiuqing Guo: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Jeffrey Haessler: Fred Hutchinson Cancer Research Center
Michael E. Hall: University of Mississippi Medical Center
Toomas Haller: University of Tartu
Kathleen Mullan Harris: University of North Carolina
Jiang He: Tulane University
Pamela Herd: Georgetown University
John K. Hewitt: University of Colorado Boulder
Ian Hickie: University of Sydney
Bertha Hidalgo: University of Alabama at Birmingham
John E. Hokanson: University of Colorado Anschutz Medical Campus
Christian Hopfer: University of Colorado Anschutz Medical Center
JoukeJan Hottenga: Vrije Universiteit Amsterdam
Lifang Hou: Northwestern University Feinberg School of Medicine
Hongyan Huang: Harvard T.H. Chan School of Public Health
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 Iacono: University of Minnesota
Marguerite R. Irvin: University of Alabama at Birmingham
Yon Ho Jee: Harvard T.H. Chan School of Public Health
Eric O. Johnson: RTI International
Yoonjung Y. Joo: Northwestern University Feinberg School of Medicine
Eric Jorgenson: Regeneron Genetics Center
Anne E. Justice: Geisinger
Yoichiro Kamatani: RIKEN Center for Integrative Medical Sciences
Robert C. Kaplan: Fred Hutchinson Cancer Research Center
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 T.H. Chan School of Public Health
Kenneth Krauter: University of Colorado
Johanna Kuusisto: University of Eastern Finland and Kuopio University Hospital
Markku Laakso: University of Eastern Finland and Kuopio University Hospital
Jessica Lasky-Su: Channing Division of Network Medicine
Wen-Jane Lee: Taichung Veterans General Hospital
James J. Lee: University of Minnesota
Daniel Levy: National Institutes of Health
Liming Li: School of Public Health, Peking University Health Science Center
Kevin Li: University of Michigan
Yuqing Li: University of California
Kuang Lin: University of Oxford
Penelope A. Lind: QIMR Berghofer Medical Research Institute
Chunyu Liu: Boston University School of Public Health
Donald M. Lloyd-Jones: Northwestern University Feinberg School of Medicine
Sharon M. Lutz: Harvard Pilgrim Health Care Institute
Jiantao Ma: National Institutes of Health
Reedik Mägi: University of Colorado Boulder
Ani Manichaikul: University of Virginia School of Medicine
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Ravi Mathur: RTI International
Nana Matoba: RIKEN Center for Integrative Medical Sciences
Patrick F. McArdle: University of Maryland School of Medicine
Matt McGue: University of Minnesota
Matthew B. McQueen: University of Colorado
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 School of Medicine
Karen L. Mohlke: University of North Carolina
Matthew Moll: Brigham and Women’s Hospital
May E. Montasser: University of Maryland School of Medicine
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Antonella Mulas: Consiglio Nazionale delle Ricerche (CNR)
Jonas B. Nielsen: Norwegian University of Science and Technology
Kari E. North: University of North Carolina at Chapel Hill
Elizabeth C. Oelsner: Columbia University Medical Center
Yukinori Okada: RIKEN Center for Integrative Medical Sciences
Valeria Orrù: Consiglio Nazionale delle Ricerche (CNR)
Nicholette D. Palmer: Wake Forest School of Medicine
Teemu Palviainen: University of Helsinki
Anita Pandit: University of Michigan
S. Lani Park: University of Hawaii Cancer Center
Ulrike Peters: Fred Hutchinson Cancer Research Center
Annette Peters: German Research Center for Environmental Health
Patricia A. Peyser: University of Michigan
Tinca J. C. Polderman: Vrije Universiteit
Nicholas Rafaels: University of Colorado Anschutz Medical Campus
Susan Redline: Brigham and Women’s Hospital
Robert M. Reed: University of Maryland School of Medicine
Alex P. Reiner: Fred Hutchinson Cancer Research Center
John P. Rice: Washington University School of Medicine
Stephen S. Rich: University of Virginia School of Medicine
Nicole E. Richmond: University of Colorado Anschutz Medical Campus
Carol Roan: University of Wisconsin-Madison
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Michael N. Rueschman: Brigham and Women’s Hospital
Valgerdur Runarsdottir: Vogur Hospital
Nancy L. Saccone: Washington University School of Medicine
David A. Schwartz: University of Colorado
Aladdin H. Shadyab: University of California, San Diego
Jingchunzi Shi: 23andMe, Inc
Suyash S. Shringarpure: 23andMe, Inc
Kamil Sicinski: University of Wisconsin-Madison
Anne Heidi Skogholt: Norwegian University of Science and Technology
Jennifer A. Smith: University of Michigan
Nicholas L. Smith: University of Washington
Nona Sotoodehnia: University of Washington
Michael C. Stallings: University of Colorado Boulder
Hreinn Stefansson: deCODE Genetics/Amgen, Inc.
Kari Stefansson: deCODE Genetics/Amgen, Inc.
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 of Bristol
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Marilyn J. Telen: Duke University School of Medicine
Khanh K. Thai: Division of Research
Hemant Tiwari: University of Alabama at Birmingham
Constance Turman: Harvard T.H. Chan School of Public Health
Thorarinn Tyrfingsson: Vogur Hospital
Tamara L. Wall: University of California San Diego
Robin G. Walters: University of Oxford
David R. Weir: University of Michigan
Scott T. Weiss: Channing Division of Network Medicine
Wendy B. White: Jackson Heart Study Undergraduate Training and Education Center, 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: Norwegian University of Science and Technology
Huichun Xu: University of Maryland School of Medicine
Lisa R. Yanek: Johns Hopkins University School of Medicine
Jie Yin: Division of Research
Kristin L. Young: University of North Carolina at Chapel Hill
Kendra A. Young: University of Colorado Anschutz Medical Campus
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
Chiara Batini: University of Leicester
Andrew W. Bergen: Oregon Research Institute
Laura J. Bierut: Washington University School of Medicine
Sean P. David: NorthShore University HealthSystem
Sarah A. Gagliano Taliun: Université de Montréal
Dana B. Hancock: RTI International
Bibo Jiang: Penn State College of Medicine
Marcus R. Munafò: University of Bristol
Thorgeir E. Thorgeirsson: deCODE Genetics/Amgen, Inc.
Dajiang J. Liu: Penn State College of Medicine
Scott Vrieze: University of Minnesota

Nature, 2022, vol. 612, issue 7941, 720-724

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 injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05477-4

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