TY - JOUR
T1 - Genetic diversity fuels gene discovery for tobacco and alcohol use
AU - 23andMe Research Team
AU - The Biobank Japan Project
AU - Saunders, Gretchen R.B.
AU - Wang, Xingyan
AU - Chen, Fang
AU - Jang, Seon Kyeong
AU - Liu, Mengzhen
AU - Wang, Chen
AU - Gao, Shuang
AU - Jiang, Yu
AU - Khunsriraksakul, Chachrit
AU - Otto, Jacqueline M.
AU - Addison, Clifton
AU - Akiyama, Masato
AU - Albert, Christine M.
AU - Aliev, Fazil
AU - Alonso, Alvaro
AU - Arnett, Donna K.
AU - Ashley-Koch, Allison E.
AU - Ashrani, Aneel A.
AU - Barnes, Kathleen C.
AU - Barr, R. Graham
AU - Bartz, Traci M.
AU - Becker, Diane M.
AU - Bielak, Lawrence F.
AU - Benjamin, Emelia J.
AU - Bis, Joshua C.
AU - Bjornsdottir, Gyda
AU - Blangero, John
AU - Bleecker, Eugene R.
AU - Boardman, Jason D.
AU - Boerwinkle, Eric
AU - Boomsma, Dorret I.
AU - Boorgula, Meher Preethi
AU - Bowden, Donald W.
AU - Brody, Jennifer A.
AU - Cade, Brian E.
AU - Chasman, Daniel I.
AU - Chavan, Sameer
AU - Chen, Yii Der Ida
AU - Chen, Zhengming
AU - Cheng, Iona
AU - Cho, Michael H.
AU - Choquet, Hélène
AU - Cole, John W.
AU - Cornelis, Marilyn C.
AU - Cucca, Francesco
AU - Curran, Joanne E.
AU - de Andrade, Mariza
AU - Dick, Danielle M.
AU - Docherty, Anna R.
AU - Duggirala, Ravindranath
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12/22
Y1 - 2022/12/22
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-022-05477-4
DO - 10.1038/s41586-022-05477-4
M3 - Article
C2 - 36477530
AN - SCOPUS:85143637078
SN - 0028-0836
VL - 612
SP - 720
EP - 724
JO - Nature
JF - Nature
IS - 7941
ER -