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.

中文翻译：

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女性特有的阿尔茨海默病风险与 tau 磷酸化过程相关：全转录组相互作用分析。


阿尔茨海默病 (AD) 患者的 tau 磷酸化水平在性别之间存在差异。疾病相互作用在转录组范围内的性别关联可以表明特定基因是否是 tau 病理学性别差异的基础；然而，目前还没有此类研究的报道。我们报告了疾病状态和性别之间的相互作用对差异基因表达的影响的首次分析，对迄今为止大脑中 3 个最大的公开病例对照研究 (N = 785) 的转录组数据进行了荟萃分析。总共 128 个与性别与 AD 相互作用显着相关的基因富含磷蛋白（错误发现率 (FDR) = 0.001）。发现 NCL (FDR = 0.002) 的过度表达存在高度且一致的关联，其磷酸化蛋白产生针对神经原纤维缠结的表位和 KIF2A (FDR = 0.005)（一种微管相关运动蛋白基因）。全转录组相互作用分析表明，Thr231、Ser199 或 Ser202 等位点的性别调节 tau 磷酸化可能会增加女性患 AD 的风险，并表明针对性别的干预和预防策略。