Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Department of Radiology and Imaging Sciences and Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Int J Mol Sci. 2020 Sep 25;21(19):7079. doi: 10.3390/ijms21197079.
Clusterin () is one of the risk genes most associated with late onset Alzheimer's disease (AD), and several genetic variants in are associated with AD risk. However, the functional role of known AD risk genetic variants in has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain-the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of ; as the number of alternative alleles () increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.
簇集蛋白（Clusterin）是与迟发性阿尔茨海默病（AD）关联最密切的风险基因之一， 中的几个遗传变异与 AD 风险相关。然而，已知 AD 风险遗传变异在簇集蛋白中的功能作用尚未得到充分探索。我们采用基于脑组织的 RNA-Seq 和加速药物研发合作组织-阿尔茨海默病（AMP-AD）全基因组测序数据的综合方法，研究了 AD 风险变异（rs7982）在簇集蛋白第 5 外显子中的剪接作用。RNA-Seq 数据来自大脑颞叶的三个区域——颞叶皮质、颞上回和海马旁回。rs7982 与簇集蛋白第 5 外显子的内含子保留（IR）显著相关；随着替代等位基因（）数量的增加，女性的 IR 率比男性下降更为显著。我们的结果表明，rs7982 通过剪接调控在 AD 发病机制中发挥性别依赖性作用。
