Identification of possible pathogenic pathways in Behçet’s disease using genome-wide association study data from two different populations

Abstract

Behc¸et's disease (BD) is a multi-system inflammatory disorder of unknown etiology. Two recent genome-wide association studies (GWASs) of BD confirmed a strong association with the MHC class I region and identified two non-HLA common genetic variations. In complex diseases, multiple factors may target different sets of genes in the same pathway and thus may cause the same disease phenotype. We therefore hypothesized that identification of disease-associated pathways is critical to elucidate mechanisms underlying BD, and those pathways may be conserved within and across populations. To identify the disease-associated pathways, we developed a novel methodology that combines nominally significant evidence of genetic association with current knowledge of biochemical pathways, protein-protein interaction networks, and functional information of selected SNPs. Using this methodology, we searched for the disease-related pathways in two BD GWASs in Turkish and Japanese case-control groups. We found that 6 of the top 10 identified pathways in both populations were overlapping, even though there were few significantly conserved SNPs/genes within and between populations. The probability of random occurrence of such an event was 2.24E À39. These shared pathways were focal adhesion, MAPK signaling, TGF-b signaling, ECM-receptor interaction, complement and coagulation cascades, and proteasome pathways. Even though each individual has a unique combination of factors involved in their disease development, the targeted pathways are expected to be mostly the same. Hence, the identification of shared pathways between the Turkish and the Japanese patients using GWAS data may help further elucidate the inflammatory mechanisms in BD pathogenesis.

A Scoring System to Evaluate the Impact of SNPs in a Path Related Context to Study Behçet’s Disease Aetiology in Japanese Population

“…These paths affect cell proliferation and cell survival. This pathway is found to be important in both Japanese and Turkish populations by Bakir-Gungor et al (2015).…”

“…In Sub-SPIA, Antigen processing and presentation, Natural killer cell mediated cytotoxicity, Th17 cell differentiation, Circadian rhythm, Insulin resistance, and Axon guidance pathways which are found to be affected by DAPath are not in the top 20 pathways. One missing pathway in DAPath is TGF-beta signaling pathway, which is known to be related to Behçet's disease (Bakir-Gungor et al 2015). This pathway is among the top 20 pathways in both SPIA and Sub-SPIA.…”

“…Mizuki et al (2010) conducted GWAS on 612 Japanese individuals with BD and 740 healthy controls. The list of significant genes was obtained using PANOGA by Bakir-Gungor et al (2015).…”

“…In (Xavier et al 2013) 508 genes have been found to be differentially expressed which have been used for further pathway analysis and association study. In (Bakir-Gungor et al 2015), pathway analysis has been performed on GWAS datasets from Turkish and Japanese populations and common pathways found to be important despite different SNP affected genes.…”

Reply to Stoimenis et al

“…2 Among the identified pathways, Stoimenis et al 1 focus on the complement and coagulation pathway since they identified three BD patients with major vessel thrombosis.…”