Genetic analyses support the contribution of mRNA N6-methyladenosine (m6A) modification to human disease heritability

• Published in: Nature genetics Vol. 52; no. 9; pp. 939 - 949
• Main Authors: Zhang, Zijie, Luo, Kaixuan, Zou, Zhongyu, Qiu, Maguanyun, Tian, Jiakun, Sieh, Laura, Shi, Hailing, Zou, Yuxin, Wang, Gao, Morrison, Jean, Zhu, Allen C., Qiao, Min, Li, Zhongshan, Stephens, Matthew, He, Xin, He, Chuan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2020; Nature Publishing Group
• Subjects: 631/208; 631/337/176; 631/337/2019; Agriculture; Animal Genetics and Genomics; Binding sites; Biomedical and Life Sciences; Biomedicine; Cancer Research; Gene expression; Gene Function; Gene mapping; Genes; Genetic analysis; Genome-wide association studies; Genomes; Heritability; Human Genetics; Lymphoblastoid cell lines; MicroRNAs; N6-methyladenosine; Proteins; Quantitative trait loci; Ribonucleic acid; RNA; RNA modification; RNA processing; RNA-binding protein; Splicing; Transcription
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-020-0644-z

N 6 -methyladenosine (m 6 A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m 6 A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m 6 A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m 6 A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m 6 A and related molecular traits suggests that the downstream effects of m 6 A are heterogeneous and context dependent. We identified proteins that mediate m 6 A effects on translation. Through integration with data from genome-wide association studies, we show that m 6 A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m 6 A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits. Quantitative trait locus (QTL) mapping of N 6 -methyladenosine (m 6 A) in human cells highlights the role of RNA-binding proteins, RNA secondary structure and context-dependent m 6 A effects. m 6 A QTLs are enriched in loci associated with immune and blood-related traits.