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 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.