Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers
Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutliers), including 1334 3' UTR and 200 intronic aOutliers, from 15,201 samples across 49 human tissues. These aOutliers exhibit unique characteristics from transcription or splicing outliers, with a pronounced RV enrichment. Mechanistically, aOutlier-RVs alter poly(A) signals and splicing sites, and perturbation indeed triggers APA events. Furthermore, we developed a Bayesian-based APA RV prediction model, which successfully pinpointed a specific set of 1799 RVs impacting 278 genes with significantly large disease effect sizes. Notably, we observed a convergence effect between rare and common cancer variants, exemplified by regulation in the DDX18 gene. Together, this study introduced an APA-enhanced framework for genome annotation, underscoring APA's role in uncovering functional RVs linked to complex traits and diseases.
Authors
- Gong‐Hong Wei (ORCID: https://orcid.org/0000-0001-6546-9334)
- Xudong Zou (ORCID: https://orcid.org/0000-0002-2958-0438)
- Ting Ni (ORCID: https://orcid.org/0000-0001-7007-1072)
- Shuhua Xu (ORCID: https://orcid.org/0000-0002-1975-1002)
- Zeyang Wang (ORCID: https://orcid.org/0000-0001-5735-0675)
- Kewei Xiong (ORCID: https://orcid.org/0000-0001-9781-9669)
- Shuxin Chen (ORCID: https://orcid.org/0000-0001-9816-0771)
- Zhaozhao Zhao (ORCID: https://orcid.org/0000-0002-5800-4077)
- Wei Li (ORCID: https://orcid.org/0000-0001-9931-5990)
- Hui Chen (ORCID: https://orcid.org/0000-0003-0582-903X)
- Lei Li (ORCID: https://orcid.org/0000-0003-3924-2544)
- Yu Chen (ORCID: https://orcid.org/0000-0003-3232-3931)
Institutions
- Shanghai Medical College of Fudan University (CN)
- University of California, Irvine (US)
- Fudan University (CN)
- Inner Mongolia University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shenzhen Bay Laboratory (CN)
- Ministry of Education (KR)
- Huashan Hospital (CN)
- State Key Laboratory of Genetic Engineering
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1038/s41467-024-55407-3
- Citations
- 7
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Westlake University
- National Natural Science Foundation of China
- Fudan University
- Science and Technology Commission of Shanghai Municipality
- Shenzhen Bay Laboratory
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Common Fund