Genetic drivers of m 6 A methylation in human brain, lung, heart and muscle.

The most prevalent post-transcriptional mRNA modification, N ⁶ -methyladenosine (m ⁶ A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m ⁶ A profiles, covering 91 individuals and 4 tissues (brain, lung, muscle and heart) from GTEx/eGTEx. We integrate these with interindividual genetic and expression variation, revealing 8,843 tissue-specific and 469 tissue-shared m ⁶ A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m ⁶ A QTLs with disease genetics, identifying 184 GWAS-colocalized m ⁶ A QTL, including brain m ⁶ A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m ⁶ A QTLs underlying expiratory flow and asthma; and muscle/heart m ⁶ A QTLs underlying coronary artery disease. Last, we predict novel m ⁶ A regulators that show preferential binding in m ⁶ A QTLs, protein interactions with known m ⁶ A regulators and expression correlation with the m ⁶ A levels of their targets. Our results provide important insights and resources for understanding both cis and trans regulation of epitranscriptomic modifications, their interindividual variation and their roles in human disease.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)