Localizing Components of Shared Transethnic Genetic Architecture of Complex Traits from GWAS Summary Data.
paper
Cited
Public
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- Authors
- Shi, Huwenbo; Burch, Kathryn S; Johnson, Ruth; Freund, Malika K; Kichaev, Gleb; Mancuso, Nicholas; Manuel, Astrid M; Dong, Natalie; Pasaniuc, Bogdan
- Year
- 2020
- Journal
- American journal of human genetics
- PMID
- 32442408
- DOI
- 10.1016/j.ajhg.2020.04.012
- PMCID
- PMC7273527
Despite strong transethnic genetic correlations reported in the literature for many complex traits, the non-transferability of polygenic risk scores across populations suggests the presence of population-specific components of genetic architecture. We propose an approach that models GWAS summary data for one trait in two populations to estimate genome-wide proportions of population-specific/shared causal SNPs. In simulations across various genetic architectures, we show that our approach yields approximately unbiased estimates with in-sample LD and slight upward-bias with out-of-sample LD. We analyze nine complex traits in individuals of East Asian and European ancestry, restricting to common SNPs (MAF > 5%), and find that most common causal SNPs are shared by both populations. Using the genome-wide estimates as priors in an empirical Bayes framework, we perform fine-mapping and observe that high-posterior SNPs (for both the population-specific and shared causal configurations) have highly correlated effects in East Asians and Europeans. In population-specific GWAS risk regions, we observe a 2.8× enrichment of shared high-posterior SNPs, suggesting that population-specific GWAS risk regions harbor shared causal SNPs that are undetected in the other GWASs due to differences in LD, allele frequencies, and/or sample size. Finally, we report enrichments of shared high-posterior SNPs in 53 tissue-specific functional categories and find evidence that SNP-heritability enrichments are driven largely by many low-effect common SNPs.
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