Genetic Analyses Support the Contribution of mRNA N(6)-methyladenosine (m(6)A) Modification to Human Disease Heritability

N(6)-methyladenosine (m(6)A) plays important roles in regulating mRNA processing. Despite rapid progress in this field, little is known about genetic determinants of m(6)A modification and their role in common diseases. In this work, we mapped quantitative trait loci (QTLs) of m(6)A peaks in 60 Yoruba lymphoblast cell lines (LCLs). We find that m(6)A-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 m(6)A and related molecular traits suggests that downstream effects of m(6)A are heterogeneous and context-dependent. We identified proteins that mediate m(6)A effects on translation. Integrating with data from genome-wide association studies (GWAS), we show that m(6)A-QTLs contribute to heritability of various immune and blood-related traits at levels comparable to splicing-QTLs and roughly half of eQTLs. Leveraging m(6)A-QTLs in a transcriptome-wide association study (TWAS) framework, we identified putative risk genes of these traits.