Allele-specific RNA N⁶-methyladenosine modifications reveal functional genetic variants in human tissues

An intricate network of cis- and trans-elements acts on RNA N⁶-methyladenosine (m⁶A), 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 m⁶A 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 m⁶A (ASm⁶A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm⁶A modifications from 25 human tissues. We also identified 1184 putative functional variants for ASm⁶A regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASm⁶A-associated genetic variants were enriched for common disease–associated and complex trait–associated risk loci, and verified that two disease risk variants can change m⁶A 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 m⁶A and genetics in human health and disease.