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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Ya Cui & Frederick J. Arnold & Fanglue Peng & Dan Wang & Jason Sheng Li & Sebastian Michels & Eric J. Wagner & Albert R. Spada & Wei Li, 2023. "Alternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36311-8
    DOI: 10.1038/s41467-023-36311-8
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    1. Zhiping Zhang & Bongmin Bae & Winston H. Cuddleston & Pedro Miura, 2023. "Coordination of alternative splicing and alternative polyadenylation revealed by targeted long read sequencing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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