Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder
Studies have shown that the levels of amyloid-β 1-42 peptide (Aβ42), total tau (T-tau), and tau phosphorylated at threonine 181 (p-tau) in cerebrospinal fluid (CSF) samples can be used as AD diagnostic biomarkers (Shaw et al, 2009; Hampel et al, 2010)
Our results of quantitative trait locus (QTL) analysis for Aβ42, T-tau/Aβ42 ratio, p-tau/Aβ42 ratio and ADAS13 (Supplementary Tables S1–S4) were illustrated in the Manhattan plots (Figure 2), showing that almost all single-nucleotide polymorphisms (SNPs) significantly associated with AD (p-value < 10−7) are located at the chromosome 19 which contains Apolipoprotein E (APOE) gene
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder. It is characterized by progressive memory loss and cognitive decline, cerebral accumulation of amyloid-β peptide (Aβ) in senile plaques and hyper-phosphorylated tau in neurofibrillary tangles (NFT) (Price and Sisodia, 1998; Mukaetova-Ladinska et al, 2015). AD patients show lower levels of CSF Aβ42 (Noguchi et al, 2005), which is negatively correlated with Aβ plaque counts in brain samples (Ikonomovic et al, 2008). The 13-item version of the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS13) was developed to measure memory and cognition for patients with mild to moderate AD (Podhorna et al, 2016). A normal ADAS13 score for a person who does not have AD is 5 (Graham et al, 2004), while 31.2 is the average score for those who have been diagnosed with AD or mild cognitive impairment (The Alzheimer’s Disease Neuroimaging Initiative et al, 2015)
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