Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways

Abstract

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Figure 1. Bird’s Eye View of Association Scan Results

The top panel summarizes the distribution of test statistics at genotyped SNPs across the genome. We used a simple chi-squared test to compare SNP allele frequencies in cases and controls and plotted the resulting -log p-values across the genome. Several p-values < 10⁻²⁰ in the MHC region were truncated. Loci where we obtained confirmatory evidence of association in follow-up samples (see Table 2) are highlighted in green. The middle panel summarizes the distribution of test statistics across the genome, after genotype imputation. We used a simple t-test to compare imputed allele counts in cases and controls and plotted the resulting –log p-values across the genome. The bottom panel displays a Q-Q plot for our test statistics. Results are plotted including all SNPs (in red), after excluding SNPs in the MHC (in orange) and after excluding all SNPs in regions of replicated association (in blue). The shaded region represents a 90% confidence interval for the test statistics.

Figure 2. Evidence for Association in Confirmed Loci

The figure summarizes evidence of association (in the discovery sample) in each region of confirmed association. Test statistics at the SNP selected for follow-up (typically, the genotyped SNP exhibiting strongest evidence for association in each locus) are highlighted with a square. Test statistics for other SNPs are drawn as circles and color coded according to the degree of linkage disequilibrium with the SNP selected for follow-up.