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Citation

Saunders, Gretchen R. B.; Wang, Xingyan; Chen, Fang; Jang, Seon-Kyeong; Liu, Mengzhen; Wang, Chen; Gao, Shuang; Jiang, Yu; Khunsriraksakul, Chachrit; & Otto, Jacqueline M., et al. (Online ahead of print). Genetic Diversity Fuels Gene Discovery for Tobacco and Alcohol Use. Nature.

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.

URL

http://dx.doi.org/10.1038/s41586-022-05477-4

Reference Type

Journal Article

Year Published

Online ahead of print

Journal Title

Nature

Author(s)

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 P.
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.
Silva, Lilian F.
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 B.
Hidalgo, Bertha
Hokanson, John E.
Hopfer, Christian J.
Hottenga, JoukeJan
Hou, Lifang
Huang, Hongyan
Hung, Yi-Jen
Hunter, David J.
Hveem, Kristian
Hwang, Shih-Jen
Hwu, Chii-Min
Iacono, William G.
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 S.
Kuusisto, Johanna
Laakso, Markku
Lasky-Su, Jessica A.
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 S.
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 K.
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
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

Article Type

Regular

Continent/Country

Nonspecific

ORCiD

Harris, KM - 0000-0001-9757-1026