An atlas of alternative polyadenylation quantitative trait loci contributing to complex trait and disease heritability

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.

Automated summary

The study presents a multi-tissue atlas of alternative polyadenylation (APA) quantitative trait loci (3 ' aQTLs) identifying approximately 0.4 million common genetic variants associated with the APA of target genes. About 16% of trait-associated variants colocalize with 3 ' aQTLs, indicating their substantial contribution to the molecular mechanisms behind human complex traits and diseases.