Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% ofworldwide deaths, respectively, due largely to broad increased risk for disease andinjury1-4. These substances are used across the globe, yet genome-wide associationstudies have focused largely on individuals of European ancestries5. Here weleveraged global genetic diversity across 3.4 million individuals from four majorclines of global ancestry (approximately 21% non-European) to power the discoveryand fine-mapping of genomic loci associated with tobacco and alcohol use, to informfunction of these loci via ancestry-aware transcriptome-wide association studies,and to evaluate the genetic architecture and predictive power of polygenic risk withinand across populations. We found that increases in sample size and genetic diversityimproved locus identification and fine-mapping resolution, and that a large majorityof the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes acrossancestry dimensions. However, polygenic risk scores developed in one ancestryperformed poorly in others, highlighting the continued need to increase sample sizesof diverse ancestries to realize any potential benefit of polygenic prediction.