TY - JOUR
T1 - A splicing transcriptome-wide association study identifies novel altered splicing for Alzheimer's disease susceptibility
AU - Sun, Yanfa
AU - Bae, Ye Eun
AU - Zhu, Jingjing
AU - Zhang, Zichen
AU - Zhong, Hua
AU - Yu, Jie
AU - Wu, Chong
AU - Wu, Lang
N1 - Funding Information:
This study is supported by the University of Hawaii Cancer Center , the Teacher Training Project of Longyan University , and the Provincial Key Science and Technology Project jointly funded by the Fujian Provincial Department of Industry and Information and the Fujian Provincial Department of Education , China (grant 2021G02015 ).
Publisher Copyright:
© 2023
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Splicing introns
KW - Susceptibility genes
KW - Transcriptome-wide association study
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U2 - 10.1016/j.nbd.2023.106209
DO - 10.1016/j.nbd.2023.106209
M3 - Article
C2 - 37354922
AN - SCOPUS:85163969334
SN - 0969-9961
VL - 184
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 106209
ER -