剪接转录组全基因组关联研究鉴定出阿尔茨海默病易感性的新型剪接改变。

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

机构信息

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.

Department of Statistics, Florida State University, Tallahassee, FL 32304, USA.

出版信息

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

DOI:10.1016/j.nbd.2023.106209

PMID:37354922

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). 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.

摘要

阿尔茨海默病（AD）是一种常见的衰老相关神经退行性疾病。据报道，选择性剪接与 AD 发病机制相关，但它们在 AD 病因学中的作用仍很大程度上难以捉摸。我们使用通过三种建模策略开发的 12 种脑组织的内含子切除表达遗传预测模型，进行了全面的剪接转录组全关联研究（spTWAS），以确定 AD 风险的候选易感性剪接内含子。总共研究了 111326 名（46828 个代理）欧洲血统的病例和 677663 名对照。经过 Bonferroni 校正（0.05/136884=3.65×10），我们鉴定出与 AD 风险相关的 233 个剪接内含子（143 个基因）的 343 个关联。精细映射分析支持 155 个可能的因果关联，对应于 55 个基因中的 83 个剪接内含子。15 个新基因（EIF2D、WDR33、SAP130、BYSL、EPHB6、MRPL43、VEGFB、PPP1R13B、TLN2、CLUHP3、LRRC37A4P、CRHR1、LINC02210、ZNF45-AS1 和 XPNPEP3）的 18 个因果剪接内含子首次被鉴定为与 AD 易感性相关。我们的研究首次确定了与 AD 风险相关的新基因和剪接内含子，这可以提高我们对 AD 病因的理解。