Genome-wide association analysis identifies three psoriasis susceptibility loci

Abstract

We carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10⁻¹¹), one at FBXL19 (rs10782001, combined P = 9 × 10⁻¹⁰) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10⁻⁸). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10⁻⁵; rs10782001, combined P = 4 × 10⁻⁸; and rs12586317, combined P = 6 × 1⁻⁵) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10⁻⁸; rs10782001, combined P = 2 × 10⁻⁶; and rs12586317, combined P = 1 × 10⁻⁶). We also replicated a recently identified association signal near RNF114 (rs495337, combined P = 2 × 10⁻⁷).

Figure 1

Evidence for psoriasis association in four genomic regions, including the three novel loci attaining genome-wide significance and the confirmed RNF114 region. The upper portion of each plot depicts association p-values for a meta-analysis of the CASP and Kiel discovery GWAS using 1000G-based imputation, while the lower portion depicts RefSeq genes and LD plots from the phase 2 HapMap-CEU sample. For each region, the most strongly associated replicated SNP is highlighted in red, as are its p-values for the discovery, replication, and combined samples.

Figure 2

Expression data for notable candidate genes within the three psoriasis-associated regions. Log₂-transformed levels of mRNA assayed by qRT-PCR are shown for normal (NN), uninvolved (PN), and lesional psoriatic (PP) skin. Figures include both individual measurements (jittered scatterplots) and box-plots summarizing the distribution. Bars and significance levels are shown for all pairwise comparisons of mean mRNA levels that are significant at a nominal (p ≤ 0.05) level.