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识别出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，我们构建了人类 3'UTR 替代多聚腺苷酸化 (APA) 数量性状位点 (3'aQTL) 的多组织图谱，其中包含约 40 万个与目标基因 APA 相关的常见遗传变异，在从 467 个组织中分离出的 46 个组织中鉴定出个体（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，从而导致数千个 APA 变化。我们基于 CRISPR 的实验表明，此类 3'aQTL 可以改变 APA 调控。此外，我们证明映射 3'aQTL 可以识别 APA 调节因子，例如 La 相关蛋白 4。最后，3'aQTL 与大约 16.1% 的性状相关变异共定位，并且与其他 QTL（例如表达 QTL）有很大不同。总之，我们的研究结果表明，3'aQTL 对人类复杂性状和疾病的分子机制有重大贡献。