Genetic diversity fuels gene discovery for tobacco and alcohol use

作者：Gretchen Saunders, Xingyan Wang, Fang Chen, Seon-Kyeong Jang, Mengzhen Liu, Chen Wang, Shuang Gao, Yu Jiang, Chachrit Khunsriraksakul, Jacqueline M. Otto, Clifton C. 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 Irene 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 C. 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 Elvestad Gabrielsen, Melanie E. Garrett, Sina A. Gharib, Christian Gieger, Nathan A. Gillespie, David C. Glahn, Scott D. Gordon, C. Charles Gu, Dongfeng Gu, Daniel Fannar Gudbjartsson, Xiuqing Guo, Jeffrey Haessler, Michael E. Hall, Toomas Haller, Kathleen Mullan Harris, Jiang He, Pamela Herd, John K. Hewitt, Ian Bernard Hickie, Bertha Hidalgo, John E. Hokanson, Christian Jean Hopfer, Jouke‐Jan Hottenga, Lifang Hou, Hongyan Huang, Yi‐Jen Hung, David John Hunter, Kristian Hveem, Shih‐Jen Hwang, Chii‐Min Hwu, William G. Iacono, Marguerite R. Irvin, Yon Ho Jee, Eric Otto Johnson, Yoonjung Yoonie Joo, Eric Jorgenson, Anne E. Justice, Yoichiro Kamatani, Robert C. Kaplan, Jaakko A. Kaprio, Sharon L. R. Kardia, Matthew C. Keller, Tanika N. Kelly, Charles L Kooperberg, Tellervo Korhonen, Peter Kraft, Kenneth S. Krauter, Johanna Kuusisto, Markku Laakso, Jessica Ann Lasky-Su, Wen‐Jane Lee, James J. Lee, Daniel Levy, Liming Li, Kevin W. Li, Yuqing Li, Kuang Lin, Penelope A. Lind, Chunyu Liu, Donald M. Lloyd‐Jones, Sharon Marie Lutz, Jiantao Ma, Reedik Mägi, Ani W Manichaikul, Nicholas G. Martin, Ravi Mathur, Nana Matoba, Patrick F. McArdle, Matt K. McGue, Matthew B. McQueen, Sarah Elizabeth Medland, Andres Metspalu, Deborah A. Meyers, Iona Y. Millwood, Braxton D. Mitchell, Karen L. Mohlke, Matthew R. Moll, May E. Montasser, Alanna C. Morrison, Antonella Mulas, Jonas Bille 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 M. Rafaels, Susan S Redline, Robert M. Reed, Alex P. Reiner, John P. Rice, Stephen S. Rich, Nicole Richmond, Carol Roan, Jerome I. Rotter, Michael Rueschman, Valgerður Rúnarsdóttir, Nancy L. Saccone, David A. Schwartz, Aladdin H. Shadyab, Jingchunzi Shi, Suyash Shringarpure, Kamil Sicinski, Anne Heidi Skogholt, Jennifer A. Smith, Nicholas L. Smith, Nona Sotoodehnia, Michael C. Stallings, Hreinn Stefánsson, Kāri Stefánsson, Jerry A. Stitzel, Xiao Wen Sun, Moin Syed, Ruth Tal‐Singer, Amy E. Taylor, Kent D. Taylor, Marilyn J. Telen, Khanh K. Thai, Hemant K. Tiwari, Constance Turman, Þórarinn Tyrfingsson, Tamara L. Wall, Robin G. Walters, David R. Weir, Scott T. Weiss, Wendy White, John B. Whitfield, Kerri L. Wiggins, Gonneke A. H. M. Willemsen, Cristen J. Willer, Bendik Slagsvold Winsvold, Huichun Xu, Lisa R. Yanek, Jie Yin, Kristin L. Young, Kendra A. Young, Bing Yu, Wei Zhao, Wei Zhou, Sebastian K. Zöllner, Luisa Zuccolo, The Biobank Japan Project, Chiara Batini, Andrew W. Bergen, Laura Jean Bierut, Sean P. David, Sarah A. Gagliano Taliun, Dana B. Hancock, Bibo Jiang, Marcus Robert Munafo, Thorgeir Elís Thorgeirsson, Dajiang J. Liu, Scott I. Vrieze · 发表于：Nature · 年份：2022 · DOI：10.1038/s41586-022-05477-4 · 被引用次数：532 · 研究领域：Genetic Associations and Epidemiology、Alcohol Consumption and Health Effects、Genetic Mapping and Diversity in Plants and Animals

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.