Genetic diversity fuels gene discovery for tobacco and alcohol use

Authors

Gretchen R. B. Saunders
Xingyan Wang
Fang Chen
Seon-Kyeong Jang
Mengzhen Liu
Chen Wang
Shuang Gao
John Blangero, The University of Texas Rio Grande ValleyFollow
Joanne E. Curran, The University of Texas Rio Grande ValleyFollow
Ravindranath Duggirala, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

12-7-2022

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 injury1,2,3,4. 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.

Comments

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Recommended Citation

Saunders, G. R., Wang, X., Chen, F., Jang, S. K., Liu, M., Wang, C., ... & Peyser, P. A. (2022). Genetic diversity fuels gene discovery for tobacco and alcohol use. Nature, 612(7941), 720-724. https://doi.org/10.1038/s41586-022-05477-4

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Nature

DOI

10.1038/s41586-022-05477-4

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics