Genetic analyses support the contribution of mRNAN6-methyladenosine (m6A) modification to human disease heritability

Abstract

N-6-methyladenosine (m(6)A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m(6)A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m(6)A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m(6)A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m(6)A and related molecular traits suggests that the downstream effects of m(6)A are heterogeneous and context dependent. We identified proteins that mediate m(6)A effects on translation. Through integration with data from genome-wide association studies, we show that m(6)A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m(6)A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits. Quantitative trait locus (QTL) mapping ofN(6)-methyladenosine (m(6)A) in human cells highlights the role of RNA-binding proteins, RNA secondary structure and context-dependent m(6)A effects. m(6)A QTLs are enriched in loci associated with immune and blood-related traits.