Data_Sheet_1_Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer’s Disease Development.DOCX

Alzheimer’s disease (AD) is the most common cause of dementia. Although genome-wide association study (GWAS) have reported hundreds of single-nucleotide polymorphisms (SNPs) and genes linked to AD, the mechanisms about how these SNPs modulate the development of AD remain largely unknown. In this study, we performed GWAS for three traits in cerebrospinal fluid (CSF) and one clinical trait in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Our analysis identified five most significant AD related SNPs (FDR < 0.05) within or proximal to APOE, APOC1, and TOMM40. One of the SNPs was co-inherited with APOE allele 4, which is the most important genetic risk factor for AD. Three of the five SNPs were located in promoter or enhancer regions, and transcription factor (TF) binding affinity calculations showed dramatic changes (| Log2FC| > 2) of three TFs (PLAG1, RREB1, and ZBTB33) for two motifs containing SNPs rs2075650 and rs157580. In addition, our GWAS showed that both rs2075650 and rs157580 were significantly associated with the poliovirus receptor-related 2 (PVRL2) gene (FDR < 0.25), which is involved in spreading of herpes simplex virus (HSV). The altered regulation of PVRL2 may increase the susceptibility AD patients to HSV and other virus infections of the brain. Our work suggests that AD is a type of immune disorder driven by viral or microbial infections of the brain during aging.

阿尔茨海默病（Alzheimer’s disease, AD）是痴呆最常见的病因。尽管全基因组关联研究（genome-wide association study, GWAS）已报道了数百个与AD相关的单核苷酸多态性（single-nucleotide polymorphisms, SNPs）及致病基因，但上述SNPs调控AD发生发展的分子机制仍在很大程度上未明确。本研究针对阿尔茨海默病神经影像倡议（Alzheimer’s Disease Neuroimaging Initiative, ADNI）队列中的3项脑脊液（cerebrospinal fluid, CSF）相关性状与1项临床性状开展了全基因组关联分析。本研究于APOE、APOC1及TOMM40基因内或其邻近区域，鉴定出5个与AD相关性最显著的SNPs（错误发现率False Discovery Rate, FDR < 0.05）。其中1个SNP与AD最重要的遗传风险因子APOE ε4等位基因共遗传。5个SNPs中的3个位于启动子或增强子区域；转录因子（Transcription Factor, TF）结合亲和力分析结果显示，针对携带rs2075650与rs157580的2个调控基序，PLAG1、RREB1及ZBTB33这3种转录因子的结合亲和力发生了显著改变（|Log₂FC| > 2）。此外，本GWAS分析显示，rs2075650与rs157580均与脊髓灰质炎病毒受体相关蛋白2（poliovirus receptor-related 2, PVRL2）基因显著相关（FDR < 0.25），该基因参与单纯疱疹病毒（herpes simplex virus, HSV）的脑内播散过程。PVRL2的调控异常可能会增加AD患者对HSV及其他脑部病毒感染的易感性。本研究结果提示，AD是一种由衰老过程中脑部病毒或微生物感染驱动的免疫紊乱性疾病。