美国芝加哥大学何川、Xin He、Matthew Stephens等研究人员合作揭示N6-甲基腺苷（m6A）修饰对人类疾病遗传力的贡献。这一研究成果于2020年6月29日在线发表于《自然—遗传学》。
Title: Genetic analyses support the contribution of mRNA N 6 -methyladenosine (m 6 A) modification to human disease heritability
Author: Zijie Zhang, Kaixuan Luo, Zhongyu Zou, Maguanyun Qiu, Jiakun Tian, Laura Sieh, Hailing Shi, Yuxin Zou, Gao Wang, Jean Morrison, Allen C. Zhu, Min Qiao, Zhongshan Li, Matthew Stephens, Xin He, Chuan He
Abstract: N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A 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 m6A and related molecular traits suggests that the downstream effects of m6A are heterogeneous and context dependent. We identified proteins that mediate m6A effects on translation. Through integration with data from genome-wide association studies, we show that m6A 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 m6A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits. Quantitative trait locus (QTL) mapping of N6-methyladenosine (m6A) in human cells highlights the role of RNA-binding proteins, RNA secondary structure and context-dependent m6A effects. m6A QTLs are enriched in loci associated with immune and blood-related traits.