Abstract
N6-methyladenosine (m6A) plays important roles in regulating mRNA processing. Despite rapid progress in this field, little is known about genetic determinants of m6A modification and their role in common diseases. In this work, we mapped quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba lymphoblast cell lines (LCLs). We find that m6A-QTLs are largely independent of expression and splicing QTLs, and are enriched with binding sites of RNA-binding proteins (RBPs), RNA structure-changing variants and transcriptional features. Joint analysis of QTLs of m6A and related molecular traits suggests that downstream effects of m6A are heterogeneous and context-dependent. We identified proteins that mediate m6A effects on translation. Integrating with data from genome-wide association studies (GWAS), we show that m6A-QTLs contribute to heritability of various immune and blood-related traits at levels comparable to splicing-QTLs and roughly half of eQTLs. Leveraging m6A-QTLs in a transcriptome-wide association study (TWAS) framework, we identified putative risk genes of these traits.
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