Pathway analysis of a genome-wide association study of ileal Crohn's disease

The aim of this study was to identify the candidate single-nucleotide polymorphisms (SNPs) and candidate mechanisms of Crohn's disease (CD) and to generate a SNP to gene to pathway hypothesis using a pathway-based approach, ICSNPathway (Identify candidate Causal SNPs and Pathways) of genome-wide association studies (GWAS). An ileal CD GWAS dataset downloaded from NCBI dbGap was used in this study, which was conducted using 297,857 SNPs in 968 CD cases and 995 controls after quality control filtering. ICSNPathway analysis was applied to the CD GWAS dataset. ICSNPathway analysis identified seven candidate SNPs, nine pathways, which provided five hypothetical biological mechanisms. First, rs4077515 to caspase recruitment domain-containing protein 9 (CARD9) to response to peptidoglycan, positive regulation of tumor necrosis factor production, response to exogenous dsRNA, positive regulation of interleukin-6 production, and positive regulation of innate immune response (nominal p≤0.002, false discovery rate [FDR]=0.027). Second, rs2066842, rs3135500, and rs5743291 to NOD2 to response to pepditoglycan, innate immune response activating signal transduction, and positive regulation of innate immune response (nominal p≤0.001, FDR=0.027). Third, rs8172678 to PPARGC1A to cellular glucose homeostasis (nominal p<0.001, FDR=0.031). Fourth, rs1050152 to SLC22A4 to cofactor transporter activity and vitamin transport (nominal p<0.001, FDR=0.044). Fifth, rs9621049 to TCN2 to vitamin transport (nominal p<0.001, FDR=0.046). In conclusion, by applying ICSNPathway analysis to CD GWAS, we identified candidate SNPs, genes involving CARD9, NOD2, PPARGC1A, SLC22A4, and TCN2, pathways, and hypothetical mechanisms, which may contribute to ileal CD susceptibility.