An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability
An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability
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DOI：
10.1038/s41588-021-00864-5
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发表时间：
2021-05-13
期刊：
影响因子：
30.8
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Li, Lei;Huang, Kai-Lieh;Li, Wei
全基因组关联研究已经确定了数千种与人类特征和疾病相关的非编码变异。然而，这些变体的功能解释是一个重大挑战。在这里，我们构建了一个多组织图谱的人3 ' UTR替代多聚腺苷酸化（阿帕）的数量性状基因座（3 ' aQTL），含有约40万个常见的遗传变异与阿帕的目标基因，确定在46个组织分离的467个个人（基因型组织表达计划）。从机制上讲，3 'aQTL可以改变poly（A）基序、RNA二级结构和RNA结合蛋白结合位点，导致成千上万的阿帕变化。我们基于CRISPR的实验表明，这样的3 'aQTL可以改变阿帕调控。此外，我们证明了定位3 'aQTL可以识别阿帕调节剂，如La相关蛋白4。最后，3 'aQTL与约16.1%的性状相关变异共定位，并且在很大程度上不同于其他QTL，如表达QTL。多组织交替多聚腺苷酸化（阿帕）数量性状基因座图谱（3 'aQTLs）鉴定了约40万个与目标基因阿帕相关的常见遗传变异。约16%的性状相关变异与3 'aQTL共定位。
Genome-wide association studies have identified thousands of noncoding variants associated with human traits and diseases. However, the functional interpretation of these variants is a major challenge. Here, we constructed a multi-tissue atlas of human 3 ' UTR alternative polyadenylation (APA) quantitative trait loci (3 ' aQTLs), containing approximately 0.4 million common genetic variants associated with the APA of target genes, identified in 46 tissues isolated from 467 individuals (Genotype-Tissue Expression Project). Mechanistically, 3 ' aQTLs can alter poly(A) motifs, RNA secondary structure and RNA-binding protein-binding sites, leading to thousands of APA changes. Our CRISPR-based experiments indicate that such 3 ' aQTLs can alter APA regulation. Furthermore, we demonstrate that mapping 3 ' aQTLs can identify APA regulators, such as La-related protein 4. Finally, 3 ' aQTLs are colocalized with approximately 16.1% of trait-associated variants and are largely distinct from other QTLs, such as expression QTLs. Together, our findings show that 3 ' aQTLs contribute substantially to the molecular mechanisms underlying human complex traits and diseases.A multi-tissue atlas of alternative polyadenylation (APA) quantitative trait loci (3 ' aQTLs) identifies approximately 0.4 million common genetic variants associated with the APA of target genes. Approximately 16% of trait-associated variants colocalize with 3 ' aQTLs.