Journal article
Genetic diversity fuels gene discovery for tobacco and alcohol use
- 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 injury. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries. 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 8.1MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-022-05477-4
Authors
+ Medical Research Council
More from this funder
- Grant:
- MC_UU_12026/2
- MC_UU_00017/1
- MC_PC_14135
- MC_PC_13049
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 612
- Issue:
- 7941
- Pages:
- 720-724
- Publication date:
- 2022-12-07
- Acceptance date:
- 2022-10-25
- DOI:
- EISSN:
-
https://ww
- ISSN:
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0028-0836
- Language:
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English
- Keywords:
- Pubs id:
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1300741
- Local pid:
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pubs:1300741
- Deposit date:
-
2022-11-09
Terms of use
- Copyright holder:
- Saunders et al.
- Copyright date:
- 2022
- Rights statement:
- © The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
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