阿尔茨海默病(Alzheimer\'sdisease,AD)是衰老个体中常见的神经退行性疾病。据报道,选择性剪接与AD的发展有关,而它们在AD病因学中的作用仍然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个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全转录组关联研究(spTWAS)。确定AD风险的候选易感性剪接内含子。共研究了111,326例(46,828个代理)病例和677,663个欧洲血统对照。在Bonferroni校正后,我们确定了233个剪接内含子(143个基因)与AD风险的343个关联(0.05/136,884=3.65×10-7)。精细作图分析支持155个可能的因果关联,对应于55个基因的83个剪接内含子。15个新基因的18个因果剪接内含子(EIF2D,WDR33,SAP130,BYSL,EPHB6,MRPL43,VEGFB,PPP1R13B,TLN2,CLUHP3,LRRC37A4P,CRHR1,LINC02210,ZNF45-AS1和XPNPEP3)首次被鉴定为与AD易感性相关。我们的研究发现了与AD风险相关的新基因和剪接内含子,从而提高我们对AD病因的认识。
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.