Female-specific risk of Alzheimer's disease is associated with tau phosphorylation processes: A transcriptome-wide interaction analysis

[摘要] The levels of tau phosphorylation differ between sexes in Alzheimer's disease (AD). Transcriptome-wide associations of sex by disease interaction could indicate whether specific genes underlie sex differences in tau pathology; however, no such study has been reported yet. We report the first analysis of the effect of the interaction between disease status and sex on differential gene expression, meta-analyzing transcriptomic data from the 3 largest publicly available case-control studies (N = 785) in the brain to date. A total of 128 genes, significantly associated with sex-AD interactions, were enriched in phosphoproteins (false discovery rate (FDR) = 0.001). High and consistent associations were found for the overexpressions of NCL (FDR = 0.002), whose phosphorylated protein generates an epitope against neurofibrillary tangles and KIF2A (FDR = 0.005), a microtubule-associated motor protein gene. Transcriptome-wide interaction analyses suggest sex-modulated tau phosphorylation, at sites like Thr231, Ser199, or Ser202 that could increase the risk of women to AD and indicate sex-specific strategies for intervention and prevention. (C) 2020 Elsevier Inc. All rights reserved.

[发布日期] 2020-12-01

[关键词] Alzheimer's disease;Female risk;Sexual dimorphism;Gene expression;Transcriptome;Expression array;Tau;Phosphorylation;Neurofibrillary tangles;NCL;KIF2A;Transcriptome-wide interaction analysis;Differential expression