Wang Hao, Rosenthal Brin Sara, Makowski Carolina, Lo Min-Tzu, Andreassen Ole A, Salem Rany M, McEvoy Linda K, Fiecas Mark, Chen Chi-Hua
Center for Multimodal Imaging and Genetics Department of Radiology University of California San Diego La Jolla California USA.
Center for Computational Biology and Bioinformatics University of California San Diego La Jolla California USA.
Alzheimers Dement (Amst). 2021 Dec 31;13(1):e12270. doi: 10.1002/dad2.12270. eCollection 2021.
Sex-dependent risk factors may underlie sex differences in Alzheimer's disease (AD).
Using sex-stratified genome-wide association studies (GWAS) of AD, we evaluated associations of 12 traits with AD through polygenic risk scores (PRS) and Mendelian randomization (MR), and explored joint genetic architecture among significant traits by genomic structural equation modeling and network analysis.
AD was associated with lower PRS for premorbid cognitive performance, intelligence, and educational attainment. MR showed a causal role for the cognition-related traits in AD, particularly among females. Their joint genetic components encompassed RNA processing, neuron projection development, and cell cycle pathways that overlap with cellular senescence. Cholesterol and C-reactive protein showed pleiotropy but no causality with AD.
Lower cognitive reserve is causally related to AD. The stronger causal link between cognitive performance and AD in females, despite similar PRS between sexes, suggest these differences may result from gene-environmental interactions accumulated over the lifespan.
性别依赖性风险因素可能是阿尔茨海默病（AD）性别差异的潜在原因。
我们利用AD的性别分层全基因组关联研究（GWAS），通过多基因风险评分（PRS）和孟德尔随机化（MR）评估了12个性状与AD的关联，并通过基因组结构方程建模和网络分析探索了显著性状之间的联合遗传结构。
AD与病前认知表现、智力和教育程度的较低PRS相关。MR显示认知相关性状在AD中起因果作用，尤其是在女性中。它们的联合遗传成分包括与细胞衰老重叠的RNA加工、神经元投射发育和细胞周期途径。胆固醇和C反应蛋白显示出多效性，但与AD无因果关系。
较低的认知储备与AD存在因果关系。尽管男女之间的PRS相似，但女性认知表现与AD之间更强的因果联系表明，这些差异可能是由一生中积累的基因-环境相互作用导致的。
