Genetic diversity fuels gene discovery for tobacco and alcohol use

23andMe Research Team, The Biobank Japan Project

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)720-724
Number of pages5
JournalNature
Volume612
Issue number7941
DOIs
StatePublished - Dec 22 2022

Bibliographical note

Funding Information:
This study was designed and carried out by the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). It was conducted by using the UK Biobank Resource under application number 16651. This study was supported by funding from US National Institutes of Health awards R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the Supplementary Note.

Funding Information:
This study was designed and carried out by the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN). It was conducted by using the UK Biobank Resource under application number 16651. This study was supported by funding from US National Institutes of Health awards R56HG011035, R01DA044283, R01DA042755 and U01DA041120 to S.V., and R01GM126479, R56HG011035, R03OD032630, R01HG011035 and R56HG012358 to D.J.L. G.R.B.S. was also supported by National Institutes of Health award T32DA050560. D.J.L. and X.W. were in part supported by the Penn State College of Medicine’s Biomedical Informatics and Artificial Intelligence Program in the Strategic Plan. A full list of acknowledgements is provided in the .

Funding Information:
The spouse of N.L. Saccone is listed as an inventor on issued U.S. patent 8080371 ‘Markers of addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 ‘Markers for addiction’, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K. Stefansson are employees of deCODE genetics/AMGEN. M. Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application ‘Biosignature discovery for substance use disorder using statistical learning’ assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests.

Publisher Copyright:
© 2022, The Author(s).

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