Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly and the leading cause of dementia in humans. Evidence shows that cellular trafficking and recycling machineries are associated with AD risk. A recent study found that the coat protein complex I (COPI)–dependent trafficking in vivo could significantly reduce amyloid plaques in the cortex and hippocampus of neurological in the AD mouse models and identified 12 single-nucleotide polymorphisms in COPI genes to be significantly associated with increased AD risk using 6,795 samples. Here, we used a large-scale GWAS dataset to investigate the potential association between the COPI genes and AD susceptibility by both SNP and gene-based tests. The results showed that only rs9898218 was associated with AD risk with P = 0.017. We further conducted an expression quantitative trait loci (eQTLs) analysis and found that rs9898218 G allele was associated with increased COPZ2 expression in cerebellar cortex with P = 0.0184. Importantly, the eQTLs analysis in whole blood further indicated that 11 of these 12 genetic variants could significantly regulate the expression of COPI genes. Hence, these findings may contribute to understand the association between COPI genes and AD susceptibility.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly and the leading cause of dementia in humans (Jiang et al, 2017; Liu et al, 2017b)
Using SNP-based test, we found that 10 of the 12 SNPs were included in this genome-wide association studies (GWASs) dataset except rs7531886 and rs34280607 variants
Using the gene-based test, our results further showed no significant association between these complex I (COPI) genes and AD susceptibility, including COPA (P = 0.3186 and 0.342), COPB1 (P = 0.6095 and 0.212), COPD/ PHLDB1 (P = 0.2942 and 0.325), COPZ1 (P = 0.3803 and 0.454), and COPZ2 (P = 0.08175 and 0.177) using PLINK and VEGAS, respectively
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly and the leading cause of dementia in humans (Jiang et al, 2017; Liu et al, 2017b). Large-scale genome-wide association studies (GWASs) have identified several novel genetic risk loci in European population, and candidate gene studies have replicated these findings in other populations (Liu et al, 2012; Liu et al, 2013b; Liu et al, 2013c; Liu et al, 2013d; Liu et al, 2014a; Liu et al, 2014b; Liu et al, 2014c; Chen et al, 2015; Li et al, 2015; Shen et al, 2015; Zhang et al, 2015; Chang et al, 2016; Li et al, 2016; Liu and Jiang, 2016; Liu et al, 2016; Ma et al, 2016; Tan et al, 2016; Zhang et al, 2016b). Whole-genome sequencing has highlighted the role of TREM2 in AD (Jiang et al, 2016; Zhang et al, 2016a; Ulland and Colonna, 2018) These AD susceptibility loci could only explain 28.57% AD genetic risk (Cuyvers and Sleegers, 2016).
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