Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases.
Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases.
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DOI：
10.1002/acn3.369
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发表时间：
2016-12
影响因子：
5.3
通讯作者：
Weale ME
中科院分区：
文献类型：
--
作者：
Gagliano SA;Pouget JG;Hardy J;Knight J;Barnes MR;Ryten M;Weale ME
我们评估了目前神经退行性疾病病因学中涉及各种细胞类型和组织类型的遗传证据，特别是与神经退行性疾病的神经炎症假说有关的证据。我们获得了帕金森病（PD）、阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）的大规模全基因组关联研究（GWAS）汇总统计数据。我们使用多发性硬化症（MS），一种中枢神经系统的自身免疫性疾病，作为阳性对照。我们应用分层LD评分回归来确定细胞类型和组织活性的功能标记，以及基因集列表是否富集了遗传遗传力。我们将我们的结果与两种基因集富集方法（Influenity Pathway Analysis和enrichr）的结果进行了比较。标记大脑区域内活性基因的注释没有显著的遗传力富集，但标记形成先天和适应性免疫系统的一部分的细胞类型内活性基因的注释有显著的遗传力富集。我们发现MS（如预期的那样）以及AD和PD也是如此。最强的信号来自适应性免疫系统（例如，T细胞）用于PD，以及来自适应性（例如，T细胞）和先天性（例如，CD 14：单核细胞的标志物，和CD 15：嗜中性粒细胞的标志物）免疫系统。来自肝脏的注释对于AD也是显著的。路径分析提供了补充结果。对于AD和PD，我们发现标记免疫细胞中基因活性的注释中遗传性显著富集。
We assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases. We obtained large‐scale genome‐wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene‐set lists were enriched for genetic heritability. We compared our results to those from two gene‐set enrichment methods (Ingenuity Pathway Analysis and enrichr). There were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results. For AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.