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

被引：12

作者：

Sun, Yanfa ^{[1
,2
]}

Bae, Ye Eun ^{[3
]}

Zhu, Jingjing ^{[2
]}

Zhang, Zichen ^{[3
]}

Zhong, Hua ^{[2
]}

Yu, Jie ^{[1
]}

Wu, Chong ^{[4
]}

Wu, Lang ^{[2
]}

机构：

[1] Longyan Univ, Fujian Prov Univ Key Lab Prevent Vet Med & Biotech, Coll Life Sci, Fujian Prov Key Lab Prevent & Control Anim Infect, Longyan 364012, Fujian, Peoples R China

[2] Univ Hawaii Manoa, Univ Hawaii Canc Ctr, Populat Sci Pacific Program, Canc Epidemiol Div, Honolulu, HI 96813 USA

[3] Florida State Univ, Dept Stat, Tallahassee, FL 32304 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

来源：

NEUROBIOLOGY OF DISEASE | 2023年 / 184卷

关键词：

Alzheimer's disease; Splicing introns; Susceptibility genes; Transcriptome-wide association study; VARIABLE SELECTION; RISK LOCI; GENOME; INSIGHTS; SCHIZOPHRENIA; METAANALYSIS; VARIANTS;

D O I：

10.1016/j.nbd.2023.106209

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 x 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.

引用

页数：8

共 72 条

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