Alternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders

Ya Cui, Frederick J. Arnold, Fanglue Peng, Dan Wang, Jason Sheng Li, Sebastian Michels, Eric J. Wagner, Albert R. Spada () and Wei Li ()
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Ya Cui: University of California, Irvine
Frederick J. Arnold: University of California Irvine
Fanglue Peng: University Baylor College of Medicine
Dan Wang: University of California, Los Angeles
Jason Sheng Li: University of California, Irvine
Sebastian Michels: University of California Irvine
Eric J. Wagner: University of Rochester Medical Center
Albert R. Spada: University of California Irvine
Wei Li: University of California, Irvine

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36311-8

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