Genome-wide pathway analysis of a genome-wide association study on Alzheimer's disease.

Abstract

The aims of this study were to identify candidate single nucleotide polymorphisms (SNPs) and mechanisms of Alzheimer's disease (AD) and to generate SNP to gene to pathway hypotheses. An AD genome-wide association study (GWAS) dataset that included 370,542 SNPs in 1,000 cases and 1,000 controls of European descent was used in this study. Identify Candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 3 candidate SNPs and 2 pathways, which provided 3 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was rs8076604 [non-synonymous coding (deleterious)] to MYO18A to negative regulation of programmed cell death [nominal P<0.001, false discovery rate (FDR) <0.043]. The second was rs2811226 (regulatory region) to ANXA1 to negative regulation of programmed cell death (nominal P<0.001, FDR 0.043). The third was rs3734166 (non-synonymous coding) to CDC25C to M phase of the mitotic cell cycle (nominal P<0.001, FDR 0.049). By applying the ICSNPathway analysis to the AD GWAS meta-analysis data, three candidate SNPs, three genes (MYO18A, ANXA1, CDC25C), 2 pathways involving negative regulation of programmed cell death and 1 pathway involving the M phase of the mitotic cell cycle were identified, which may contribute to AD susceptibility.