Analysis of Alzheimer's disease Polygenic Risk Scores using RNA-sequencing provides further novel biological pathways
Analysis of Alzheimer's disease Polygenic Risk Scores using RNA-sequencing provides further novel biological pathways
复制标题
使用 RNA 测序分析阿尔茨海默病多基因风险评分提供了更多新颖的生物学途径
DOI：
10.1101/2022.06.29.22276952
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Crawford K
中科院分区：
文献类型：
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作者：
Crawford K
多基因风险评分（PRS）已被广泛采用作为测量常见变异责任的工具，并且已被证明可以预测阿尔茨海默病（AD）发展的终生风险。然而，PRS 和 AD 发病机制之间的关系在很大程度上尚不清楚。我们的目的是解决与 PRS 相关的下游分子后果方面的一些知识差距。我们还对病例/对照分类中被破坏的生物机制以及同一个体对 PRS 的反应进行了直接比较。我们对最大的人脑来源队列样本（288 名个体；小脑和颞叶皮层；MayoRNAseq；AMP-AD）的转录组与匹配的 AD 遗传和基因表达数据（WGS；bulk-brain）进行了综合计算分析 RNA 测序）。病例/对照和 PRS 分析中的差异表达基因几乎没有重叠，但对常见的被破坏的生物学机制达成了共识。发现先前 AD GWAS 涉及的基因仅在颞叶皮层中相对于 PRS 显着富集。我们确定了先前与 AD 相关的机制，包括免疫/应激反应、脂质/胆固醇/脂肪酸代谢、内体、死亡/凋亡、神经元过程、衰老和神经胶质细胞的参与。我们还提供了新的证据，证明细胞结构（包括高尔基体和内质网以及线粒体功能）与 AD 密切相关。病例/对照分类与 PRS 相关的大部分常见生物学机制表明，PRS 分层可用于无法获得合适病例/对照样本的研究或在临床试验中选择具有高和低 PRS 的个体。
Polygenic risk scores (PRS) have been widely adopted as a tool for measuring common variant liability and it has been shown to predict lifetime risk of Alzheimer’s disease (AD) development. However, the relationship between PRS and AD pathogenesis is largely unknown. We aimed to address some of the knowledge gaps with respect to the downstream molecular consequences associated with PRS. We also make a direct comparison of the disrupted biological mechanisms in a case/control classification and in response to PRS in the same individuals.We performed an integrative computational analysis of the transcriptome of the largest human brain-derived cohort sample (288 individuals; cerebellum and temporal cortex; MayoRNAseq; AMP-AD) with matched AD genetic and gene-expression data (WGS; bulk-brain RNA-seq). There was little overlap in terms of differentially expressed genes in case/control and PRS analyses, but a consensus of commonly disrupted biological mechanisms. Genes implicated by previous AD GWAS were found to be significantly enriched with respect to PRS in temporal cortex only. We identified mechanisms that were previously implicated in AD, including immune/stress response, lipid/cholesterol/fatty acid metabolism, endosome, death/apoptosis, neuronal processes, ageing and the involvement of glial cells. We also provide novel evidence for the significant involvement in AD of cellular structures, including the Golgi apparatus and endoplasmic reticulum as well as mitochondrial function.The largely common biological mechanisms between a case/control classification and in association with PRS suggests that PRS stratification can be used for studies where suitable case/control samples are not available or the selection of individuals with high and low PRS in clinical trials.