OA08 GWAS meta-analysis of ankylosing spondylitis and Behçet's disease identifies novel MHC-I-opathy genes

Abstract

Abstract Background/Aims Spondyloarthropathies (SpA) and Behçet's disease (BD) have clinical and HLA locus overlap and have been grouped under MHC-I-opathy [1]. Genetic overlap can help elucidate MHC-I-opathy pathogenesis. Ankylosing spondylitis (AS) is a primary SpA. Here, a cluster-based approach helps to identify overlapping loci between AS and BD of even modest significance. Methods Association clustering methods such as OASIS [2] reduce the multiple-testing burden and are therefore more powerful than single variant analysis for identifying modest genetic effects. Here, two large genome-wide association studies (GWAS) of AS (921 cases, 907 controls) and BD (1215 cases and 1278 healthy controls) from Turkiye, were subjected to OASIS meta-analyses to identify common non-HLA loci [3, 4]. Statistics used to identify significant loci included the novel OASIS locus index (OLI), defined as the product of maximum -logP at a locus with the ratio of actual to predicted number of significant SNPs. Results GWAS for both diseases had the highest significance at the HLA-locus. OASIS avoids the proportional signals problem, inherent in GWAS, by separately analysing highly significant loci (P < 10-8). Hence, of the 234 independent modestly significant non-HLA loci, there were 16 loci common to both AS and BD (Figure 1). These included known MHC-I-opathy loci, 1p31.3 for IL23R (P = 5.37 E-06, OLI = 52.7) and 13q14.11 for LACC1 (P = 7.41 E-06, OLI= 65.3) [1, 5]. Novel loci included 3p21.31 containing CCR9 (P = 2.46 E-05, OLI=25.8), 3q22.3 containing CLDN18 (P = 5.37 E-05, OLI=31.4) and 4q27-4q28.1 containing FGF2 (P = 1.1 E-04, OLI=29.5). Conclusion Five loci containing pathologically relevant genes for MHC-I-opathy were identified using a cluster-based approach in AS and BD GWAS datasets. These large meta-analyses will help identify pathogenic pathways for MHC-I-opathy, an entity that has so far largely remained elusive [6]. Disclosure M. Saeed: None.