Allele-specific RNAN6-methyladenosine modifications reveal functional genetic variants in human tissues

An intricate network of cis - and trans -elements acts on RNA N 6 -methyladenosine (m 6 A), which in turn may affect gene expression and, ultimately, human health. A complete understanding of this network requires new approaches to accurately measure the subtle m 6 A differences arising from genetic variants, many of which have been associated with common diseases. To address this gap, we developed a method to accurately and sensitively detect transcriptome-wide allele-specific m 6 A (ASm 6 A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm 6 A modifications from 25 human tissues. We also identified 1184 putative functional variants for ASm 6 A regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASm 6 A-associated genetic variants were enriched for common disease–associated and complex trait–associated risk loci, and verified that two disease risk variants can change m 6 A modification status. Together, this work provides a tool to detangle the dynamic network of RNA modifications at the allelic level and highlights the interplay of m 6 A and genetics in human health and disease.