Genetic drivers of m6A methylation in human brain, lung, heart and muscle
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nihms-1795394.pdf
Description
Accepted version
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5.69 MB
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Checksum (MD5)
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Author(s)
Xiong, Xushen
Hou, Lei
Park, Yongjin P
Molinie, Benoit
Ardlie, Kristin G
Aguet, François
Gregory, Richard I
Kellis, Manolis
Date Issued
2021
Journal
Nature Genetics
Publisher
Springer Science and Business Media LLC
Citation
Xiong, Xushen, Hou, Lei, Park, Yongjin P, Molinie, Benoit, Ardlie, Kristin G et al. 2021. "Genetic drivers of m6A methylation in human brain, lung, heart and muscle." Nature Genetics, 53 (8).
Version
Author's final manuscript
Abstract
The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays diverse RNA-regulatory roles, but its genetic control in human tissues remains uncharted. Here we report 129 transcriptome-wide m6A 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 m6A quantitative trait loci (QTLs), which are modestly enriched in, but mostly orthogonal to, expression QTLs. We integrate m6A QTLs with disease genetics, identifying 184 GWAS-colocalized m6A QTL, including brain m6A QTLs underlying neuroticism, depression, schizophrenia and anxiety; lung m6A QTLs underlying expiratory flow and asthma; and muscle/heart m6A QTLs underlying coronary artery disease. Last, we predict novel m6A regulators that show preferential binding in m6A QTLs, protein interactions with known m6A regulators and expression correlation with the m6A 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.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/S41588-021-00890-3
