Ancestry-specific regulatory and disease architectures are likely due to cell-type-specific gene-by-environment interactions

Multi-ancestry genome-wide association studies (GWAS) have highlighted the existence of variants with ancestry-specific effect sizes. Understanding where and why these ancestry-specific effects occur is fundamental to understanding the genetic basis of human diseases and complex traits. Here, we characterized genes differentially expressed across ancestries (ancDE genes) at the cell-type level by leveraging single-cell RNA-seq data in peripheral blood mononuclear cells for 21 individuals with East Asian (EAS) ancestry and 23 individuals with European (EUR) ancestry (172K cells); then, we tested if variants surrounding those genes were enriched in disease variants with ancestry-specific effect sizes by leveraging ancestry-matched GWAS of 31 diseases and complex traits (average N = 90K and 267K in EAS and EUR, respectively). We observed that ancDE genes tend to be cell-type-specific, to be enriched in genes interacting with the environment, and in variants with ancestry-specific disease effect sizes, suggesting the impact of shared cell-type-specific gene-by-environment (GxE) interactions between regulatory and disease architectures. Finally, we illustrated how GxE interactions might have led to ancestry-specific MCL1 expression in B cells, and ancestry-specific allele effect sizes in lymphocyte count GWAS for variants surrounding MCL1. Our results imply that large single-cell and GWAS datasets in diverse populations are required to improve our understanding on the effect of genetic variants on human diseases.