Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisms (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18 × 10(-8), odds ratio (OR)=1.27, 95% confidence interval (CI)=1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NFκBIA.

Figure 1. Results of genome-wide meta-analysis

The negative decadic logarithm of the corresponding P-value from the meta-analysis is shown for each SNP, according to chromosome. All markers that passed quality control criteria, were available in all three GWAS and showed no heterogeneity between the studies were used for plotting. The plot was created with the software environment R version 2.11.1 (Team, 2007). The established PsA loci HLA-C and TNIP1 are highlighted by grey arrows, while the follow-up loci are tagged by black arrows. The novel risk locus at REL is highlighted by a red arrow. The HLA region stands out clearly from all other loci. For better scaling the Y-axis was limited to a maximum value of -log10(P)=10, thereby truncating the HLA signal at this value.

Figure 2. Regional plot of the REL locus

Regional plot of the negative decadic logarithm of the combined P-values from the imputed meta-analysis of three GWAS panels. A window of 500 kb around the lead SNP rs13017599 (blue filled circle) is shown. The three GWAS panels were imputed with CEU haplotypes generated by the 1000 Genomes Project (August 2010 release) as a reference. The magnitude of linkage disequilibrium (LD) with the central SNP rs13017599, measured by r², is reflected by the color of each SNP symbol (color coding: see upper right corner of the plot).