Genetic analyses support the contribution of mRNA N-methyladenosine (mA) modification to human disease heritability.

N-methyladenosine (mA) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of mA modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of mA peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that mA 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 mA and related molecular traits suggests that the downstream effects of mA are heterogeneous and context dependent. We identified proteins that mediate mA effects on translation. Through integration with data from genome-wide association studies, we show that mA 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 mA QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits.