Faculty, Staff and Student Publications
Publication Date
12-1-2022
Journal
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 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.
Keywords
Humans, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Multifactorial Inheritance, Risk Factors, Tobacco Use, Alcohol Drinking, Transcriptome, Sample Size, Genetic Loci, Internationality, Europe
DOI
10.1038/s41586-022-05477-4
PMID
36477530
PMCID
PMC9771818
PubMedCentral® Posted Date
12-7-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes