Publication Date
2-3-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-36311-8
PMID
36737438
PMCID
PMC9898543
PubMedCentral® Posted Date
2-3-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Polyadenylation, Transcriptome, Amyotrophic Lateral Sclerosis, Genome-Wide Association Study, Parkinson Disease, 3' Untranslated Regions, Computational neuroscience, Gene regulation
Abstract
Alternative polyadenylation (APA) plays an essential role in brain development; however, current transcriptome-wide association studies (TWAS) largely overlook APA in nominating susceptibility genes. Here, we performed a 3' untranslated region (3'UTR) APA TWAS (3'aTWAS) for 11 brain disorders by combining their genome-wide association studies data with 17,300 RNA-seq samples across 2,937 individuals. We identified 354 3'aTWAS-significant genes, including known APA-linked risk genes, such as SNCA in Parkinson's disease. Among these 354 genes, ~57% are not significant in traditional expression- and splicing-TWAS studies, since APA may regulate the translation, localization and protein-protein interaction of the target genes independent of mRNA level expression or splicing. Furthermore, we discovered ATXN3 as a 3'aTWAS-significant gene for amyotrophic lateral sclerosis, and its modulation substantially impacted pathological hallmarks of amyotrophic lateral sclerosis in vitro. Together, 3'aTWAS is a powerful strategy to nominate important APA-linked brain disorder susceptibility genes, most of which are largely overlooked by conventional expression and splicing analyses.