Cross-ancestry genetic architecture and prediction for cholesterol traits

Abstract

AbstractWhile cholesterol is essential for human life, a high level of cholesterol is closely linked with the risk of cardiovascular diseases. Genome-wide association studies (GWASs) have been successful to identify genetic variants associated with cholesterol, which have been conducted mostly in white European populations. Consequently, it remains mostly unknown how genetic effects on cholesterol vary across ancestries. Here, we estimate cross-ancestry genetic correlation to address questions on how genetic effects are shared across ancestries for cholesterol. We find significant genetic heterogeneity between ancestries for total- and LDL-cholesterol. Furthermore, we show that single nucleotide polymorphisms (SNPs), which have concordant effects across ancestries for cholesterol, are more frequently found in the regulatory region, compared to the other genomic regions. Indeed, the positive genetic covariance between ancestries is mostly driven by the effects of the concordant SNPs, whereas the genetic heterogeneity is attributed to the discordant SNPs. We also show that the predictive ability of the concordant SNPs is significantly higher than the discordant SNPs in the cross-ancestry polygenic prediction. The list of concordant SNPs for cholesterol is available in GWAS Catalog (https://www.ebi.ac.uk/gwas/; details are in web resources section). These findings have relevance for the understanding of shared genetic architecture across ancestries, contributing to the development of clinical strategies for polygenic prediction of cholesterol in cross-ancestral settings