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.

N ⁶ -甲基腺苷 (m ⁶ A) 在调节信使 RNA 加工中发挥重要作用。尽管该领域取得了快速进展，但人们对 m ⁶ A 修饰的遗传决定因素及其在常见疾病中的作用知之甚少。在本研究中，我们绘制了 60 个约鲁巴 (YRI) 类淋巴母细胞系中 m ⁶ A 峰的数量性状位点 (QTL)。我们发现 m ⁶ A QTL 在很大程度上独立于表达和剪接 QTL，并且富含 RNA 结合蛋白的结合位点、RNA 结构改变变体和转录特征。 m ⁶ A 的 QTL 和相关分子性状的联合分析表明，m ⁶ A 的下游效应是异质的且依赖于环境。我们鉴定了介导 m ⁶ A 对翻译的影响的蛋白质。通过与全基因组关联研究的数据整合，我们发现 m ⁶ A QTL 对各种免疫和血液相关性状的遗传性有贡献，其水平与剪接 QTL 和大约一半的表达 QTL 相当。通过在全转录组关联研究框架中利用 m ⁶ A QTL，我们确定了这些性状的假定风险基因。