Genetic diversity fuels gene discovery for tobacco and alcohol use
Gretchen 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 Alıev, Álvaro 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, Gyða Björnsdóttir, John Blangero, Eugene R. Bleecker, Jason D. Boardman, Eric Boerwinkle, Dorret I. Boomsma, Meher P. 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 de 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 A. Gillespie, David C. Glahn, Scott D. Gordon, C. Charles Gu, Dongfeng Gu, Daníel F. Guðbjartsson, Xiuqing Guo, Jeffrey Haessler, Michael E. Hall, Toomas Haller, Kathleen Mullan Harris, Jiang He, Pamela Herd, John K. Hewitt, Ian B. Hickie, Bertha Hidalgo, John E. Hokanson, Christian J. Hopfer, Jouke‐Jan Hottenga, Lifang Hou, Hongyan Huang, Yi‐Jen Hung, David J. Hunter, Kristian Hveem, Shih‐Jen Hwang, Chii‐Min Hwu, William G. Iacono, Marguerite R. Irvin, Yon Ho Jee, Eric O. Johnson, Yoonjung Yoonie Joo, Eric Jorgenson, Anne E. Justice, Yoichiro Kamatani, Robert C. Kaplan, Jaakko Kaprio, Sharon L. R. Kardia, Matthew C. Keller
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.