
Genetic diversity fuels gene discovery for tobacco and alcohol use.
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.
Duke Scholars
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Related Subject Headings
- Transcriptome
- Tobacco Use
- Sample Size
- Risk Factors
- Multifactorial Inheritance
- Internationality
- Humans
- Genome-Wide Association Study
- Genetic Variation
- Genetic Predisposition to Disease
Citation

Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Transcriptome
- Tobacco Use
- Sample Size
- Risk Factors
- Multifactorial Inheritance
- Internationality
- Humans
- Genome-Wide Association Study
- Genetic Variation
- Genetic Predisposition to Disease