Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
Nat Genet. 2021 Jul;53(7):994-1005. doi: 10.1038/s41588-021-00864-5. Epub 2021 May 13.
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.
全基因组关联研究已经确定了数千个与人类特征和疾病相关的非编码变异。然而，这些变异的功能解释是一个主要挑战。在这里，我们构建了一个人类 3'UTR 可变多聚腺苷酸化（APA）数量性状基因座（3'aQTL）的多组织图谱，其中包含大约 467 个人的 46 个组织中分离出的与目标基因 APA 相关的约 400 万个常见遗传变异（基因型-组织表达项目）。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，导致数千个 APA 变化。我们基于 CRISPR 的实验表明，这种 3'aQTL 可以改变 APA 调节。此外，我们证明了映射 3'aQTL 可以识别 APA 调节剂，如 La 相关蛋白 4。最后，3'aQTL 与大约 16.1%的与特征相关的变体共定位，并且与其他 QTL（如表达 QTL）在很大程度上不同。总之，我们的研究结果表明，3'aQTL 对人类复杂特征和疾病的分子机制有很大贡献。
