Genetic diversity fuels gene discovery for tobacco and alcohol use

Gretchen R B Saunders^#¹, Xingyan Wang^#², Fang Chen^#², Seon-Kyeong Jang^#¹, Mengzhen Liu^#¹, Chen Wang^#², Shuang Gao², Yu Jiang³, Chachrit Khunsriraksakul², Jacqueline M Otto¹, Clifton Addison⁴, Masato Akiyama^{5

6}, Christine M Albert^{7

8}, Fazil Aliev⁹, Alvaro Alonso¹⁰, Donna K Arnett¹¹, Allison E Ashley-Koch^{12

13}, Aneel A Ashrani¹⁴, Kathleen C Barnes^{15

16}, R Graham Barr¹⁷, Traci M Bartz^{18

19}, Diane M Becker²⁰, Lawrence F Bielak²¹, Emelia J Benjamin^{22

23}, Joshua C Bis¹⁸, Gyda Bjornsdottir²⁴, John Blangero²⁵, Eugene R Bleecker²⁶, Jason D Boardman²⁷, Eric Boerwinkle²⁸, Dorret I Boomsma²⁹, Meher Preethi Boorgula¹⁵, Donald W Bowden³⁰, Jennifer A Brody¹⁸, Brian E Cade^{31

32

33}, Daniel I Chasman⁸, Sameer Chavan¹⁵, Yii-Der Ida Chen³⁴, Zhengming Chen^{35

36}, Iona Cheng^{37

38}, Michael H Cho^{39

40}, Hélène Choquet⁴¹, John W Cole^{42

43}, Marilyn C Cornelis⁴⁴, Francesco Cucca⁴⁵, Joanne E Curran²⁵, Mariza de Andrade⁴⁶, Danielle M Dick⁹, Anna R Docherty^{47

48

49}, Ravindranath Duggirala²⁵, Charles B Eaton⁵⁰, Marissa A Ehringer^{51

52}, Tõnu Esko⁵³, Jessica D Faul⁵⁴, Lilian Fernandes Silva⁵⁵, Edoardo Fiorillo⁵⁶, Myriam Fornage^{28

57}, Barry I Freedman⁵⁸, Maiken E Gabrielsen⁵⁹, Melanie E Garrett^{12

13}, Sina A Gharib^{18

60

61}, Christian Gieger⁶², Nathan Gillespie⁴⁸, David C Glahn⁶³, Scott D Gordon⁶⁴, Charles C Gu⁶⁵, Dongfeng Gu⁶⁶, Daniel F Gudbjartsson^{24

67}, Xiuqing Guo⁶⁸, Jeffrey Haessler⁶⁹, Michael E Hall⁷⁰, Toomas Haller⁵³, Kathleen Mullan Harris⁷¹, Jiang He^{72

73}, Pamela Herd⁷⁴, John K Hewitt^{51

75}, Ian Hickie⁷⁶, Bertha Hidalgo⁷⁷, John E Hokanson⁷⁸, Christian Hopfer⁷⁹, JoukeJan Hottenga²⁹, Lifang Hou⁴⁴, Hongyan Huang^{80

81}, Yi-Jen Hung⁸², David J Hunter⁸³, Kristian Hveem^{59

84

85}, Shih-Jen Hwang⁸⁶, Chii-Min Hwu⁸⁷, William Iacono¹, Marguerite R Irvin⁷⁷, Yon Ho Jee⁸⁰, Eric O Johnson^{88

89}, Yoonjung Y Joo^{44

90}, Eric Jorgenson⁹¹, Anne E Justice^{92

93}, Yoichiro Kamatani^{5

94}, Robert C Kaplan^{69

95}, Jaakko Kaprio⁹⁶, Sharon L R Kardia²¹, Matthew C Keller^{51

75}, Tanika N Kelly^{72

73}, Charles Kooperberg^{19

69}, Tellervo Korhonen⁹⁶, Peter Kraft^{80

81}, Kenneth Krauter⁹⁷, Johanna Kuusisto^{98

99}, Markku Laakso⁹⁸, Jessica Lasky-Su¹⁰⁰, Wen-Jane Lee¹⁰¹, James J Lee¹, Daniel Levy⁸⁶, Liming Li¹⁰², Kevin Li¹⁰³, Yuqing Li³⁷, Kuang Lin³⁵, Penelope A Lind^{104

105

106}, Chunyu Liu¹⁰⁷, Donald M Lloyd-Jones¹⁰⁸, Sharon M Lutz^{109

110}, Jiantao Ma^{86

111}, Reedik Mägi⁵², Ani Manichaikul¹¹², Nicholas G Martin⁶⁴, Ravi Mathur⁸⁸, Nana Matoba^{5

113}, Patrick F McArdle¹¹⁴, Matt McGue¹, Matthew B McQueen¹¹⁵, Sarah E Medland¹⁰⁴, Andres Metspalu⁵³, Deborah A Meyers²⁶, Iona Y Millwood^{35

36}, Braxton D Mitchell^{114

116}, Karen L Mohlke¹¹⁷, Matthew Moll^{39

40}, May E Montasser¹¹⁴, Alanna C Morrison²⁸, Antonella Mulas⁵⁶, Jonas B Nielsen^{59

118}, Kari E North⁹³, Elizabeth C Oelsner¹⁷, Yukinori Okada^{119

120

121

122}, Valeria Orrù⁵⁶, Nicholette D Palmer³⁰, Teemu Palviainen⁹⁶, Anita Pandit¹⁰³, S Lani Park¹²³, Ulrike Peters^{69

124}, Annette Peters^{125

126

127}, Patricia A Peyser²¹, Tinca J C Polderman^{128

129}, Nicholas Rafaels¹⁵, Susan Redline^{31

32

130}, Robert M Reed¹³¹, Alex P Reiner^{69

124}, John P Rice¹³², Stephen S Rich¹¹², Nicole E Richmond⁷⁸, Carol Roan¹³³, Jerome I Rotter⁶⁸, Michael N Rueschman³¹, Valgerdur Runarsdottir¹³⁴, Nancy L Saccone^{65

135}, David A Schwartz¹³⁶, Aladdin H Shadyab¹³⁷, Jingchunzi Shi¹³⁸, Suyash S Shringarpure¹³⁸, Kamil Sicinski¹³³, Anne Heidi Skogholt⁵⁹, Jennifer A Smith^{21

54}, Nicholas L Smith^{124

139

140}, Nona Sotoodehnia^{18

141}, Michael C Stallings^{51

75}, Hreinn Stefansson²⁴, Kari Stefansson^{24

142}, Jerry A Stitzel⁵¹, Xiao Sun⁷², Moin Syed¹, Ruth Tal-Singer¹⁴³, Amy E Taylor^{144

145

146}, Kent D Taylor⁶⁸, Marilyn J Telen¹², Khanh K Thai⁴¹, Hemant Tiwari¹⁴⁷, Constance Turman^{80

81}, Thorarinn Tyrfingsson¹³⁴, Tamara L Wall¹⁴⁸, Robin G Walters^{35

36}, David R Weir⁵⁴, Scott T Weiss¹⁰⁰, Wendy B White¹⁴⁹, John B Whitfield⁶⁴, Kerri L Wiggins¹⁵⁰, Gonneke Willemsen²⁹, Cristen J Willer^{151

152

153}, Bendik S Winsvold^{59

154

155}, Huichun Xu¹¹⁴, Lisa R Yanek²⁰, Jie Yin⁴¹, Kristin L Young¹⁵⁶, Kendra A Young⁷⁸, Bing Yu²⁸, Wei Zhao²¹, Wei Zhou^{153

157}, Sebastian Zöllner^{158

159}, Luisa Zuccolo^{144

146

160}; 23andMe Research Team; Biobank Japan Project; Chiara Batini¹⁶¹, Andrew W Bergen^{162

163}, Laura J Bierut¹³², Sean P David^{164

165}, Sarah A Gagliano Taliun^{166

167

168}, Dana B Hancock⁸⁸, Bibo Jiang², Marcus R Munafò^{144

145

169}, Thorgeir E Thorgeirsson²⁴, Dajiang J Liu¹⁷⁰, Scott Vrieze¹⁷¹

Affiliations

¹ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
² Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
³ Department of Epidemiology & Population Health at Stanford University, Stanford, CA, USA.
⁴ Jackson Heart Study (JHS) Graduate Training and Education Center (GTEC), Department of Epidemiology and Biostatistics, School of Public Health, Jackson State University, Jackson, MS, USA.
⁵ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶ Department of Ocular Pathology and Imaging Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
⁷ Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
¹⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹¹ Dean's Office and Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY, USA.
¹² Department of Medicine and Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, USA.
¹³ Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
¹⁴ Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
¹⁵ Division of Biomedical Informatics & Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁶ Tempus, Chicago, IL, USA.
¹⁷ Department of Medicine, Columbia University Medical Center, New York, NY, USA.
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁰ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²¹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²² Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
²³ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²⁴ deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
²⁵ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
²⁶ Department of Medicine, University of Arizona, Tucson, AZ, USA.
²⁷ Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ Netherlands Twin Register, Dept Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³⁰ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
³² Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
³³ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
³⁴ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁶ MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁷ Department of Epidemiology & Biostatistics, University of California, San Francisco, CA, USA.
³⁸ UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
³⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁰ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴¹ Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, USA.
⁴² Department of Neurology, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
⁴³ Division of Vascular Neurology, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁴ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴⁵ University of Sassari, Sassari SS, Italy.
⁴⁶ Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
⁴⁷ Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁴⁸ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Virginia, USA.
⁴⁹ Huntsman Mental Health Institute, Salt Lake City, UT, USA.
⁵⁰ Department of Family Medicine, Brown University, Providence, RI, USA.
⁵¹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁵² Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
⁵³ Institute of Genomics, University of Tartu, Tartu, Estonia.
⁵⁴ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵⁵ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
⁵⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Italy.
⁵⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁸ Department of Internal Medicine-Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵⁹ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁶⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶¹ Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶² Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶³ Department of Psychiatry & Behavioral Sciences, Boston Children's Hospital & Harvard Medical School, Boston, MA, USA.
⁶⁴ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶⁵ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
⁶⁶ Department of Epidemiology and Key Laboratory of Cardiovascular Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶⁷ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁶⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶⁹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁷⁰ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁷¹ Department of Sociology and the Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
⁷² Department of Epidemiology, Tulane University, New Orleans, LA, USA.
⁷³ Translational Sciences Institute, Tulane University, New Orleans, LA, USA.
⁷⁴ McCourt School of Public Policy, Georgetown University, Washington, DC, USA.
⁷⁵ Department Of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
⁷⁶ Youth Mental Health & Technology Team, Brain and Mind Centre, University of Sydney, Sydney, Australia.
⁷⁷ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁷⁸ Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷⁹ Department of Psychiatry, University of Colorado Anschutz Medical Center, Denver, CO, USA.
⁸⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸¹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸² Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan.
⁸³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁴ HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁸⁵ Department of Research, Innovation and Education, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸⁶ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁸⁷ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸⁸ GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, NC, USA.
⁸⁹ Fellow Program, RTI International, Research Triangle Park, NC, USA.
⁹⁰ Institute of Data Science, Korea University, Seoul, South Korea.
⁹¹ Regeneron Genetics Center, Tarrytown, NY, USA.
⁹² Department of Population Health Sciences, Geisinger, Danville, PA, USA.
⁹³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹⁴ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁹⁵ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁹⁶ Institute for Molecular Medicine Finland - FIMM, University of Helsinki, Helsinki, Finland.
⁹⁷ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
⁹⁸ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
⁹⁹ Center for Medicine and Clinical Research, Kuopio University Hospital, Kuopio, Finland.
¹⁰⁰ Brigham and Women's Hospital, Department of Medicine, Channing Division of Network Medicine, Boston, MA, USA.
¹⁰¹ Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan.
¹⁰² Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
¹⁰³ Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁴ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁰⁵ School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
¹⁰⁶ School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
¹⁰⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁰⁸ Departments of Preventive Medicine, Medicine, and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁰⁹ Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
¹¹⁰ Department of Biostatics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹¹ Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
¹¹² Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹¹³ Department of Genetics, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹⁴ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹⁵ Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.
¹¹⁶ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
¹¹⁷ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹¹⁸ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
¹¹⁹ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹²⁰ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹²¹ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
¹²² Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹²³ Population Sciences of the Pacific Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹²⁴ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹²⁵ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
¹²⁶ Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilians University Munich, Munich, Germany.
¹²⁷ German Centre for Cardiovascular Research, DZHK, Partner Site Munich, Munich, Germany.
¹²⁸ Department of Clinical Developmental Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹²⁹ Department of Child and Adolescent Psychiatry, Amsterdam UMC, Amsterdam, The Netherlands.
¹³⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹³¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹³² Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
¹³³ Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA.
¹³⁴ SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
¹³⁵ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹³⁶ Division of Pulmonary Sciences and Critical Care Medicine; Department of Medicine and Immunology, University of Colorado, Aurora, CO, USA.
¹³⁷ Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
¹³⁸ 23andMe, Inc, Sunnyvale, CA, USA.
¹³⁹ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.
¹⁴⁰ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA.
¹⁴¹ Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁴² Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴³ COPD Foundation, Washington, DC, USA.
¹⁴⁴ MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
¹⁴⁵ National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.
¹⁴⁶ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁴⁷ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁴⁸ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
¹⁴⁹ Jackson Heart Study Undergraduate Training and Education Center, Tougaloo College, Tougaloo, MS, USA.
¹⁵⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁵¹ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
¹⁵² Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁵³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁵⁴ Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁵⁵ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁵⁶ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁵⁷ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁵⁸ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁵⁹ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
¹⁶⁰ Health Data Science Centre, Fondazione Human Technopole, Milan, Italy.
¹⁶¹ Department of Population Health Sciences, University of Leicester, Leicester, UK.
¹⁶² Oregon Research Institute, Springfield, OR, USA.
¹⁶³ BioRealm, LLC, Walnut, CA, USA.
¹⁶⁴ Outcomes Research Network & Department of Family Medicine, NorthShore University HealthSystem, Evanston, IL, USA.
¹⁶⁵ Department of Family Medicine, University of Chicago, Chicago, IL, USA.
¹⁶⁶ Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
¹⁶⁷ Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada.
¹⁶⁸ Research Centre, Montréal Heart Institute, Montréal, Québec, Canada.
¹⁶⁹ School of Psychological Science, University of Bristol, Bristol, UK.
¹⁷⁰ Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA. dajiang.liu@psu.edu.
¹⁷¹ Department of Psychology, University of Minnesota, Minneapolis, MN, USA. vrieze@umn.edu.

^# Contributed equally.

PMID: 36477530
PMCID: PMC9771818
DOI: 10.1038/s41586-022-05477-4

Genetic diversity fuels gene discovery for tobacco and alcohol use

Gretchen R B Saunders et al. Nature. 2022 Dec.

. 2022 Dec;612(7941):720-724.

doi: 10.1038/s41586-022-05477-4. Epub 2022 Dec 7.

Authors

Affiliations

¹ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
² Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.
³ Department of Epidemiology & Population Health at Stanford University, Stanford, CA, USA.
⁴ Jackson Heart Study (JHS) Graduate Training and Education Center (GTEC), Department of Epidemiology and Biostatistics, School of Public Health, Jackson State University, Jackson, MS, USA.
⁵ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁶ Department of Ocular Pathology and Imaging Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
⁷ Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
¹⁰ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹¹ Dean's Office and Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY, USA.
¹² Department of Medicine and Duke Comprehensive Sickle Cell Center, Duke University School of Medicine, Durham, NC, USA.
¹³ Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
¹⁴ Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
¹⁵ Division of Biomedical Informatics & Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁶ Tempus, Chicago, IL, USA.
¹⁷ Department of Medicine, Columbia University Medical Center, New York, NY, USA.
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁰ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²¹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²² Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
²³ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
²⁴ deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
²⁵ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
²⁶ Department of Medicine, University of Arizona, Tucson, AZ, USA.
²⁷ Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA.
²⁸ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁹ Netherlands Twin Register, Dept Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³⁰ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³¹ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA.
³² Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
³³ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
³⁴ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁵ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁶ MRC Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁷ Department of Epidemiology & Biostatistics, University of California, San Francisco, CA, USA.
³⁸ UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
³⁹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁰ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴¹ Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA, USA.
⁴² Department of Neurology, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA.
⁴³ Division of Vascular Neurology, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁴ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴⁵ University of Sassari, Sassari SS, Italy.
⁴⁶ Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
⁴⁷ Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁴⁸ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Virginia, USA.
⁴⁹ Huntsman Mental Health Institute, Salt Lake City, UT, USA.
⁵⁰ Department of Family Medicine, Brown University, Providence, RI, USA.
⁵¹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁵² Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
⁵³ Institute of Genomics, University of Tartu, Tartu, Estonia.
⁵⁴ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁵⁵ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
⁵⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Italy.
⁵⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁸ Department of Internal Medicine-Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁵⁹ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁶⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶¹ Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶² Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶³ Department of Psychiatry & Behavioral Sciences, Boston Children's Hospital & Harvard Medical School, Boston, MA, USA.
⁶⁴ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶⁵ Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
⁶⁶ Department of Epidemiology and Key Laboratory of Cardiovascular Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁶⁷ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
⁶⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁶⁹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁷⁰ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁷¹ Department of Sociology and the Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
⁷² Department of Epidemiology, Tulane University, New Orleans, LA, USA.
⁷³ Translational Sciences Institute, Tulane University, New Orleans, LA, USA.
⁷⁴ McCourt School of Public Policy, Georgetown University, Washington, DC, USA.
⁷⁵ Department Of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
⁷⁶ Youth Mental Health & Technology Team, Brain and Mind Centre, University of Sydney, Sydney, Australia.
⁷⁷ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
⁷⁸ Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷⁹ Department of Psychiatry, University of Colorado Anschutz Medical Center, Denver, CO, USA.
⁸⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸¹ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁸² Institute of Preventive Medicine, National Defense Medical Center, New Taipei City, Taiwan.
⁸³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁴ HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁸⁵ Department of Research, Innovation and Education, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸⁶ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁸⁷ Section of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
⁸⁸ GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, NC, USA.
⁸⁹ Fellow Program, RTI International, Research Triangle Park, NC, USA.
⁹⁰ Institute of Data Science, Korea University, Seoul, South Korea.
⁹¹ Regeneron Genetics Center, Tarrytown, NY, USA.
⁹² Department of Population Health Sciences, Geisinger, Danville, PA, USA.
⁹³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹⁴ Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁹⁵ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁹⁶ Institute for Molecular Medicine Finland - FIMM, University of Helsinki, Helsinki, Finland.
⁹⁷ Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
⁹⁸ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
⁹⁹ Center for Medicine and Clinical Research, Kuopio University Hospital, Kuopio, Finland.
¹⁰⁰ Brigham and Women's Hospital, Department of Medicine, Channing Division of Network Medicine, Boston, MA, USA.
¹⁰¹ Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan.
¹⁰² Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
¹⁰³ Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁴ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁰⁵ School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia.
¹⁰⁶ School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
¹⁰⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁰⁸ Departments of Preventive Medicine, Medicine, and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁰⁹ Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
¹¹⁰ Department of Biostatics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹¹ Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
¹¹² Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
¹¹³ Department of Genetics, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹⁴ Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹⁵ Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.
¹¹⁶ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
¹¹⁷ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
¹¹⁸ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
¹¹⁹ Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
¹²⁰ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹²¹ Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan.
¹²² Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
¹²³ Population Sciences of the Pacific Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹²⁴ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹²⁵ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
¹²⁶ Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig Maximilians University Munich, Munich, Germany.
¹²⁷ German Centre for Cardiovascular Research, DZHK, Partner Site Munich, Munich, Germany.
¹²⁸ Department of Clinical Developmental Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
¹²⁹ Department of Child and Adolescent Psychiatry, Amsterdam UMC, Amsterdam, The Netherlands.
¹³⁰ Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹³¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹³² Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
¹³³ Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA.
¹³⁴ SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
¹³⁵ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
¹³⁶ Division of Pulmonary Sciences and Critical Care Medicine; Department of Medicine and Immunology, University of Colorado, Aurora, CO, USA.
¹³⁷ Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
¹³⁸ 23andMe, Inc, Sunnyvale, CA, USA.
¹³⁹ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.
¹⁴⁰ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA.
¹⁴¹ Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁴² Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹⁴³ COPD Foundation, Washington, DC, USA.
¹⁴⁴ MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, UK.
¹⁴⁵ National Institute for Health Research Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.
¹⁴⁶ Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁴⁷ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
¹⁴⁸ Department of Psychiatry, University of California San Diego, San Diego, CA, USA.
¹⁴⁹ Jackson Heart Study Undergraduate Training and Education Center, Tougaloo College, Tougaloo, MS, USA.
¹⁵⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁵¹ Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
¹⁵² Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁵³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁵⁴ Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
¹⁵⁵ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁵⁶ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁵⁷ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁵⁸ Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
¹⁵⁹ Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
¹⁶⁰ Health Data Science Centre, Fondazione Human Technopole, Milan, Italy.
¹⁶¹ Department of Population Health Sciences, University of Leicester, Leicester, UK.
¹⁶² Oregon Research Institute, Springfield, OR, USA.
¹⁶³ BioRealm, LLC, Walnut, CA, USA.
¹⁶⁴ Outcomes Research Network & Department of Family Medicine, NorthShore University HealthSystem, Evanston, IL, USA.
¹⁶⁵ Department of Family Medicine, University of Chicago, Chicago, IL, USA.
¹⁶⁶ Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
¹⁶⁷ Department of Neurosciences, Université de Montréal, Montréal, Québec, Canada.
¹⁶⁸ Research Centre, Montréal Heart Institute, Montréal, Québec, Canada.
¹⁶⁹ School of Psychological Science, University of Bristol, Bristol, UK.
¹⁷⁰ Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA. dajiang.liu@psu.edu.
¹⁷¹ Department of Psychology, University of Minnesota, Minneapolis, MN, USA. vrieze@umn.edu.

^# Contributed equally.

PMID: 36477530
PMCID: PMC9771818
DOI: 10.1038/s41586-022-05477-4

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 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.

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Conflict of interest statement

The spouse of N.L. Saccone is listed as an inventor on issued U.S. patent 8080371 ‘Markers of addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 ‘Markers for addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K. Stefansson are employees of deCODE genetics/AMGEN. M. Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application ‘Biosignature discovery for substance use disorder using statistical learning’ assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests.

Figures

**Fig. 1. Ancestry composition and effect size moderation.**
a, Ancestry compositions of contributing studies (each point is a study). Colours are coded by primary ancestry of individuals in the cohort. Studies with less than 90% of individuals assignable to a single ancestry group are shown in grey. Ancestry component 3 was a north–south EUR cline, which was omitted here as we did not conduct meta-analyses stratified by northern versus southern Europe. TOPMed, Trans-Omics for Precision Medicine. b, Extent of effect size moderation as a function of the same ancestry dimensions as shown in a. The full moderation results are in Supplementary Table 2. Each point in b represents an independent variant with the standardized MDS component coefficient from our trans-ancestry models (that is, γ) along the x axes, and the corresponding mean difference in effect sizes (β) for the ancestry-stratified meta-analysis of the given ancestry versus all other ancestries along the y axes. The grey circles indicate variants showing little to no evidence of effect size heterogeneity across ancestry, whereas the coloured circles represent variants with adequate evidence of effect size heterogeneity. The plots highlight that the majority of variants have similar effect sizes across all ancestry clines, with some potentially interesting exceptions in which the variant effects sizes differ substantially between ancestry clines.

**Fig. 2. Within-ancestry and across-ancestry performance of polygenic scores in an independent target sample (Add Health).**
a, Incremental variance explained for each target ancestry group. The colour of the stacked bars indicates the ancestry from which the polygenic score was derived; the total height of each set of the stacked bars (and 95% confidence intervals) correspond to the total variance explained by all four ancestry-stratified scores combined. For example, in the target EUR subsample, non-EUR polygenic scores add little over and above the EUR score. Note that some comparisons are underpowered to detect differences in predictive accuracy across ancestry (see Supplementary Note). Heritabilities, estimated by LD score regression, of each phenotype–ancestry combination are depicted by the grey dashed bar (with 95% confidence intervals) and corresponding sample sizes; these represent the maximum expected accuracy of the polygenic risk score (PRS). b, The manner in which the phenotype mean in the target sample changes as a function of the EUR PRS deciles. c, Results from an interaction model, in which each phenotype was modelled as a function of an interaction between the EUR-based PRS and target ancestry (coded as a factor with EUR ancestry as the reference and scores scaled within ancestry). The bands around each line denote the 95% confidence intervals. Significant interactions are noted with text. Using SmkInit as an example, the purple line represents the predicted proportion of regular smokers as a function of the EUR PRS in the EUR subsample of Add Health, the blue lines show the predicted proportion of regular smokers by standard deviation of the EUR PRS in the EAS subsample, and so on. In this case, the magnitude of the association between the EUR-based PRS and SmkInit (that is, the slope) was significantly greater in the EUR target ancestry than all other ancestries. Full PRS results are in Supplementary Table 12.

**Extended Data Fig. 1. Ancestry space of studies contributing to meta-analysis (panel a), versus individuals from TOPMed and 1000 Genomes (panel b).**
The meta-regression within the MEMO model requires specification of ancestry clines. To ensure consistency in the meaning of ancestry clines across all five MEMO analyses (one for each phenotype) we created a single multidimensional scaling solution based on allele frequencies from all phenotypes in all participating cohorts. These solutions are plotted in panel a (circles correspond to TOPMed cohorts, squares are all other cohorts which used imputed microarray genotypes, and triangles are 1000 Genomes ancestry groups). Colors of points correspond to the primary assigned ancestry of each cohort (studies with < 90% of individuals coming from a single ancestry group are shown in grey). Panel b shows projection of principal components (after OADP transformation) of TOPMed individuals onto PCs of 1000 Genomes individuals, in colored triangles. Each 1000 Genomes individual is colored by their known ancestry. This PC information was used in assigning ancestry to TOPMed individuals for the purpose of reference panel creation (individuals of South Asian ancestry were not included in analyses). The PCs in panel b were reordered or reversed in some cases to align with panel a. These transformations are noted in the axis labels.

**Extended Data Fig. 2. Multi-ancestry meta-analysis Manhattan plots.**
Black horizontal line corresponds to P = 5 × 10⁻⁹, the GWAS significance threshold used for all analyses. Note that some y-axis scales are discontinuous to better illustrate variants with very small P-values (e.g., the Drinks per Week y-axis is cut at 30 with a maximum value of 307.7, denoting a P-value of 1.9 × 10⁻³⁰⁸). All P-values are from two-sided statistical tests.

**Extended Data Fig. 3. Tissue expression and brain cell type enrichment in high priority genes.**
Panel a shows tissue expression enrichment in ‘high priority’ genes. We define high priority genes here as those located nearest to the variants in fine-mapped credible intervals containing less than five variants. These genes were compared to ‘control’ genes identified in the same way, but from variants in credible intervals with PIP < 0.01 from the trans-ancestry fine-mapping. The x-axis denotes GTEx tissue types. The y-axis represents relative risk estimates comparing high priority to control genes. Panel b shows similar relative risk comparisons with 39 brain cell types. Data are presented as relative risk values with error bars denoting bootstrapped 95% confidence intervals. Further details on estimating relative risk are included in the Supplementary Note section ‘Functional enrichment’.

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References

1. World Health Organization. Tobacco. WHOhttps://www.who.int/news-room/fact-sheets/detail/tobacco (2022).
1. World Health Organization. Alcohol. WHOhttps://www.who.int/news-room/fact-sheets/detail/alcohol (2022).
1. World Health Organization. The top 10 causes of death. WHOhttps://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (2020).
1. Griswold MG, et al. Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2018;392:1015–1035. - PMC - PubMed
1. Liu M, et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 2019;51:237–244. - PMC - PubMed

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Genetic diversity fuels gene discovery for tobacco and alcohol use

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Genetic diversity fuels gene discovery for tobacco and alcohol use

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