Genetic diversity fuels gene discovery for tobacco and alcohol use
Authors: Saunders Gretchen R. B. , Wang Xingyan , Chen Fang , Jang Seon-Kyeong , Liu Mengzhen , Wang Chen , Gao Shuang , Jiang Yu , Khunsriraksakul Chachrit , Otto Jacqueline M. , Addison Clifton , Akiyama Masato , Albert Christine M. , Aliev Fazil , Alonso Alvaro , Arnett Donna K. , Ashley-Koch Allison E. , Ashrani Aneel A. , Barnes Kathleen C. , Barr R. Graham , Bartz Traci M. , Becker Diane M. , Bielak Lawrence F. , Benjamin Emelia J. , Bis Joshua C. , Bjornsdottir Gyda , Blangero John , Bleecker Eugene R. , Boardman Jason D. , Boerwinkle Eric , Boomsma Dorret I. , Boorgula Meher Preethi , Bowden Donald W. , Brody Jennifer A. , Cade Brian E. , Chasman Daniel I. , Chavan Sameer , Chen Yii-Der Ida , Chen Zhengming , Cheng Iona , Cho Michael H. , Choquet Hélène , Cole John W. , Cornelis Marilyn C. , Cucca Francesco , Curran Joanne E. , de Andrade Mariza , Dick Danielle M. , Docherty Anna R. , Duggirala Ravindranath , Eaton Charles B. , Ehringer Marissa A. , Esko Tõnu , Faul Jessica D. , Fernandes Silva Lilian , Fiorillo Edoardo , Fornage Myriam , Freedman Barry I. , Gabrielsen Maiken E. , Garrett Melanie E. , Gharib Sina A. , Gieger Christian , Gillespie Nathan , Glahn David C. , Gordon Scott D. , Gu Charles C. , Gu Dongfeng , Gudbjartsson Daniel F. , Guo Xiuqing , Haessler Jeffrey , Hall Michael E. , Haller Toomas , Harris Kathleen Mullan , He Jiang , Herd Pamela , Hewitt John K. , Hickie Ian , Hidalgo Bertha , Hokanson John E. , Hopfer Christian , Hottenga JoukeJan , Hou Lifang , Huang Hongyan , Hung Yi-Jen , Hunter David J. , Hveem Kristian , Hwang Shih-Jen , Hwu Chii-Min , Iacono William , Irvin Marguerite R. , Jee Yon Ho , Johnson Eric O. , Joo Yoonjung Y. , Jorgenson Eric , Justice Anne E. , Kamatani Yoichiro , Kaplan Robert C. , Kaprio Jaakko , Kardia Sharon L. R. , Keller Matthew C. , Kelly Tanika N. , Kooperberg Charles , Korhonen Tellervo , Kraft Peter , Krauter Kenneth , Kuusisto Johanna , Laakso Markku , Lasky-Su Jessica , Lee Wen-Jane , Lee James J. , Levy Daniel , Li Liming , Li Kevin , Li Yuqing , Lin Kuang , Lind Penelope A. , Liu Chunyu , Lloyd-Jones Donald M. , Lutz Sharon M. , Ma Jiantao , Mägi Reedik , Manichaikul Ani , Martin Nicholas G. , Mathur Ravi , Matoba Nana , McArdle Patrick F. , McGue Matt , McQueen Matthew B. , Medland Sarah E. , Metspalu Andres , Meyers Deborah A. , Millwood Iona Y. , Mitchell Braxton D. , Mohlke Karen L. , Moll Matthew , Montasser May E. , Morrison Alanna C. , Mulas Antonella , Nielsen Jonas B. , North Kari E. , Oelsner Elizabeth C. , Okada Yukinori , Orrù Valeria , Palmer Nicholette D. , Palviainen Teemu , Pandit Anita , Park S. Lani , Peters Ulrike , Peters Annette , Peyser Patricia A. , Polderman Tinca J. C. , Rafaels Nicholas , Redline Susan , Reed Robert M. , Reiner Alex P. , Rice John P. , Rich Stephen S. , Richmond Nicole E. , Roan Carol , Rotter Jerome I. , Rueschman Michael N. , Runarsdottir Valgerdur , Saccone Nancy L. , Schwartz David A. , Shadyab Aladdin H. , Shi Jingchunzi , Shringarpure Suyash S. , Sicinski Kamil , Skogholt Anne Heidi , Smith Jennifer A. , Smith Nicholas L. , Sotoodehnia Nona , Stallings Michael C. , Stefansson Hreinn , Stefansson Kari , Stitzel Jerry A. , Sun Xiao , Syed Moin , Tal-Singer Ruth , Taylor Amy E. , Taylor Kent D. , Telen Marilyn J. , Thai Khanh K. , Tiwari Hemant , Turman Constance , Tyrfingsson Thorarinn , Wall Tamara L. , Walters Robin G. , Weir David R. , Weiss Scott T. , White Wendy B. , Whitfield John B. , Wiggins Kerri L. , Willemsen Gonneke , Willer Cristen J. , Winsvold Bendik S. , Xu Huichun , Yanek Lisa R. , Yin Jie , Young Kristin L. , Young Kendra A. , Yu Bing , Zhao Wei , Zhou Wei , Zöllner Sebastian , Zuccolo Luisa ,   23andMe Research Team,   The Biobank Japan Project, Batini Chiara , Bergen Andrew W. , Bierut Laura J. , David Sean P. , Gagliano Taliun Sarah A. , Hancock Dana B. , Jiang Bibo , Munafò Marcus R. , Thorgeirsson Thorgeir E. , Liu Dajiang J. , Vrieze Scott 
Published: December 2022

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.