A splicing transcriptome-wide association study identifies novel altered splicing for Alzheimer's disease susceptibility

Yanfa Sun; Ye Eun Bae; Jingjing Zhu; Zichen Zhang; Hua Zhong; Jie Yu; Chong Wu; Lang Wu

doi:10.1016/j.nbd.2023.106209

A splicing transcriptome-wide association study identifies novel altered splicing for Alzheimer's disease susceptibility

Neurobiol Dis. 2023 Aug:184:106209. doi: 10.1016/j.nbd.2023.106209. Epub 2023 Jun 22.

Authors

Yanfa Sun¹, Ye Eun Bae², Jingjing Zhu³, Zichen Zhang², Hua Zhong³, Jie Yu⁴, Chong Wu⁵, Lang Wu⁶

Affiliations

¹ College of Life Science, Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Fujian Provincial Universities Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Longyan University, Longyan, Fujian 364012, PR China; Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
² Department of Statistics, Florida State University, Tallahassee, FL 32304, USA.
³ Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
⁴ College of Life Science, Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Fujian Provincial Universities Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Longyan University, Longyan, Fujian 364012, PR China.
⁵ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: cwu18@mdanderson.org.
⁶ Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA. Electronic address: lwu@cc.hawaii.edu.

PMID: 37354922
DOI: 10.1016/j.nbd.2023.106209

Abstract

Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × 10^-7). Fine-mapping analyses supported 155 likely causal associations corresponding to 83 splicing introns of 55 genes. Eighteen causal splicing introns of 15 novel genes (EIF2D, WDR33, SAP130, BYSL, EPHB6, MRPL43, VEGFB, PPP1R13B, TLN2, CLUHP3, LRRC37A4P, CRHR1, LINC02210, ZNF45-AS1, and XPNPEP3) were identified for the first time to be related to AD susceptibility. Our study identified novel genes and splicing introns associated with AD risk, which can improve our understanding of the etiology of AD.

Keywords: Alzheimer's disease; Splicing introns; Susceptibility genes; Transcriptome-wide association study.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Cell Adhesion Molecules / genetics
Genetic Predisposition to Disease / genetics
Humans
Kruppel-Like Transcription Factors / genetics
Neurodegenerative Diseases*
Polymorphism, Single Nucleotide
RNA Splicing
Repressor Proteins / genetics
Transcriptome

Substances

ZNF45 protein, human
Repressor Proteins
Kruppel-Like Transcription Factors
BYSL protein, human
Cell Adhesion Molecules