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

Abstract

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 (3QTLs), 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, 3QTLs could alter polyA motifs and RNA-binding protein binding sites, leading to thousands of APA changes. Importantly, 3QTLs can be used to interpret [~]16.1% of trait-associated variants and are largely distinct from other QTLs such as eQTLs. The genetic basis of APA (3QTLs) thus represent a novel molecular phenotype to explain a large fraction of non-coding variants and to provide new insights into complex traits and disease etiologies.\n\nHighlightsO_LIThe first atlas of human 3QTLs: [~]0.4 million genetic variants associated with alternative polyadenylation of target genes across 46 tissues from 467 individuals\nC_LIO_LI3QTLs could alter polyA motifs and RNA-binding protein binding sites\nC_LIO_LI3QTLs can be used to interpret [~]16.1% of trait-associated variants\nC_LIO_LIMany disease-associated 3QTLs contribute to phenotype independent of gene expression\nC_LI