Genetic Basis of Alternative Polyadenylation as an Emerging Molecular Phenotype for Human Traits and Diseases. Genetic Basis of Alternative Polyadenylation as an Emerging Molecular Phenotype for Human Traits and Diseases

Genome-wide association studies have identified thousands of non-coding variants that are statistically associated with human traits and diseases. However, functional interpretation of these variants remains a major challenge. Here, we describe the first atlas of human 3’-UTR alternative polyadenylation (APA) Quantitative Trait Loci (3′aQTLs), i.e. ~0.4 million genetic variants associated with APA of target genes across 46 Genotype-Tissue Expression (GTEx) tissues from 467 individuals. APA occurs in approximately 70% of human genes and substantively impacts cellular proliferation, differentiation and tumorigenesis. Mechanistically, 3′aQTLs could alter polyA motifs and RNA-binding protein binding sites, leading to thousands of APA changes. Importantly, 3′aQTLs can be used to interpret ~16.1% of trait-associated variants and are largely distinct from other QTLs such as eQTLs. These 3′aQTLs thus represent the genetic basis of APA as a novel molecular phenotype to explain a large fraction of non-coding variants and to provide new insights into complex traits and disease etiologies. Overall design: Examination of alternative polyadenylation and gene expression upon LARP4 KD in HEK293T cells.