Open AccessGenetic drivers of m6A methylation in human brain, lung, heart and muscle
Author(s) -
Xushen Xiong,
Lei Hou,
Yongjin Park,
Benoit Molinié,
Richard I. Gregory,
M Kellis
Publication year - 2021
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-021-00890-3
Subject(s) - biology , quantitative trait locus , expression quantitative trait loci , genome wide association study , genetics , transcriptome , epigenomics , dna methylation , regulation of gene expression , gene expression , gene , single nucleotide polymorphism , genotype
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.