GWAS meta-analysis of Axial spondyloarthritis and Behçet's disease identifies CXCR6 as a novel MHC-I-opathy gene

Objective: Axial spondyloarthritis (AxSpA) and Behçet's disease (BD) have clinical and HLA locus overlap and have been grouped under MHC-I-opathy. This study aimed to identify overlapping loci between AxSpA and BD to help elucidate MHC-I-opathy pathogenesis. Methods: Association clustering methods, such as OASIS, reduce the multiple-testing burden and are more powerful than single variant analysis for identifying modest genetic effects. Two large publically available genome-wide association studies (GWAS) of AxSpA (921 cases, 907 controls) and BD (1215 cases and 1278 healthy controls) from Turkiÿe, were subjected to OASIS meta-analyses to identify common non-HLA loci. Statistics used to identify significant loci included the novel OASIS locus index (OLI). Expression analysis was performed using GEO datasets, GSE181364 for AxSpA and GSE209567 for BD. STRING network analysis was performed. Results: GWAS for both diseases had the highest significance at the HLA-I locus. Of the 234 independent modestly significant non-HLA loci, there were 15 loci common to both AxSpA and BD. These included known MHC-I-opathy loci, 1p31.3 for IL23R ( P = 5.37x10 ^-6 , OLI=52.7) and 13q14.11 for LACC1 ( P =7.41x10 ^-6 , OLI=65.3). A novel locus identified in this study is 3p21.31 containing CXCR6 ( P =2.46x10 ^-5 , OLI=25.8). The locus 3p22.3 had the highest overall OLI (81.3) and the most significant SNP at this locus (rs2291897; P =1.82x10 ^-5 ), is an intronic variant in the gene FBXL2 . However, this association was specific for BD only. Conclusion: Several loci containing pathologically relevant genes for MHC-I-opathy were identified here, using a cluster-based approach in AxSpA and BD GWAS, with CXCR6 being a novel target.