Fine mapping of eight psoriasis susceptibility loci

Abstract

Previous studies have identified 41 independent genome-wide significant psoriasis susceptibility loci. After our first psoriasis genome-wide association study, we designed a custom genotyping array to fine-map eight genome-wide significant susceptibility loci known at that time (IL23R, IL13, IL12B, TNIP1, MHC, TNFAIP3, IL23A and RNF114) enabling genotyping of 2269 single-nucleotide polymorphisms (SNPs) in the eight loci for 2699 psoriasis cases and 2107 unaffected controls of European ancestry. We imputed these data using the latest 1000 Genome reference haplotypes, which included both indels and SNPs, to increase the marker density of the eight loci to 49 239 genetic variants. Using stepwise conditional association analysis, we identified nine independent signals distributed across six of the eight loci. In the major histocompatibility complex (MHC) region, we detected three independent signals at rs114255771 (P = 2.94 × 10(-74)), rs6924962 (P = 3.21 × 10(-19)) and rs892666 (P = 1.11 × 10(-10)). Near IL12B we detected two independent signals at rs62377586 (P = 7.42 × 10(-16)) and rs918518 (P = 3.22 × 10(-11)). Only one signal was observed in each of the TNIP1 (rs17728338; P = 4.15 × 10(-13)), IL13 (rs1295685; P = 1.65 × 10(-7)), IL23A (rs61937678; P = 1.82 × 10(-7)) and TNFAIP3 (rs642627; P = 5.90 × 10(-7)) regions. We also imputed variants for eight HLA genes and found that SNP rs114255771 yielded a more significant association than any HLA allele or amino-acid residue. Further analysis revealed that the HLA-C*06-B*57 haplotype tagged by this SNP had a significantly higher odds ratio than other HLA-C*06-bearing haplotypes. The results demonstrate allelic heterogeneity at IL12B and identify a high-risk MHC class I haplotype, consistent with the existence of multiple psoriasis effectors in the MHC.

Figure 1

Regional association plot for MHC. Association plots for MHC region in the unconditional round, the first conditional round and the second conditional round are shown in (a), (b) and (c), respectively. The horizontal axis represents the base position on chromosome 6 (from 27 to 34 Mb on build 37). The left-vertical axis represents the negative log (base 10) of the P-value in the corresponding round (denoted by the circles) and the right-vertical axis represents the recombination rate (in cM/Mb) (denoted by the blue lines). The color coding for the circles is used to represent the linkage disequilibrium with the most significant SNP in the region in each round.

Figure 2

Regional association plot for IL12B. Association plots for the IL12B region in the unconditional round and the first conditional round are shown in (a) and (b), respectively. The horizontal axis represents the base position on chromosome 5 (from 158.7 to 159 Mb on build 37). The left-vertical axis represents the negative log (base 10) of the P-value in the corresponding round (denoted by the circles) and the right-vertical axis represents the recombination rate (in cM/Mb) (denoted by the blue lines). The color coding for the circles is used to represent the linkage disequilibrium with the most significant SNP in the region in each round.

Figure 3

Regional association plot for IL13, TNIP1, TNFAIP3 and IL23A. Association plots for the IL13, TNIP1, TNFAIP3 and IL23A regions are shown in (a), (b), (c) and (d), respectively. The horizontal axis represents the base position of the corresponding region. The left-vertical axis represents the negative log (base 10) of the P-value in the corresponding round (denoted by the circles) and the right-vertical axes represents the recombination rate (in cM/Mb) (denoted by the blue lines). The color coding for the circles is used to represent the linkage disequilibrium with the most significant SNP in the region in each round.

Figure 4

Comparison of results from this study with results from Knight et al and Feng et al. Comparison of the results from this study with the results from Knight et al and Feng et al is shown in (a) and (b), respectively. The SNPs on the vertical axes represent the significant SNPs from this study and the SNPs on the horizontal axes represent the significant SNPs from Knight et al and Feng et al in (a) and (b), respectively. The blocks (corresponding to each SNP on the horizontal axes versus each SNP on the vertical axes) with the color coding represents the strength of linkage disequilibrium between the corresponding SNPs, which was calculated as a measure to show corroboration between the studies at hand.