Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

Abstract

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

Figure 1. Manhattan plot of single SNP association test results.

(a) Chinese GWAS meta-analysis with 1,588 cases and 3,546 controls; (b) Caucasian GWAS meta-analysis with 3,496 cases and 5,186 controls; (c) trans-ethnic GWAS meta-analysis with 5,084 cases and 8,732 controls. The x-axis indicates the chromosomal position. The y-axis indicates the –log10 P values of genome-wide SNP associations from each GWAS meta-analysis using logistic regression. The horizontal green line represents the genome-wide significance threshold of P=5.0 × 10⁻⁸. Blue dots indicate the association results of SNPs within the 41 known psoriasis risk loci; red dots indicate the association results of SNPs within the four new psoriasis risk loci; grey dots indicate the association results of SNPs outside the 45 psoriasis risk loci.

Figure 2. The regional association plots of ZMIZ1 showing locus heterogeneity.

The relative location of annotated genes and the direction of transcription are shown in the lower portion of the figure, and the chromosomal position is shown on the x axis. The blue line shows the recombination rate (estimated from HapMap data of CEU, CHB and combined population) across the region (right y axis), and the left y axis shows the significance of the SNP associations (−log10 P). The square indicates the SNPs for conditional analysis (these are the top or secondary SNPs); the circle labelled with rs IDs are reported psoriasis susceptibility SNPs. All circles and squares are colour filled based on the heterogeneity results (I²) in our trans-ethnic meta analysis. (a,b) Unconditional and conditional logistic association results of Caucasian, (c, d) unconditional and conditional logistic association results of Chinese.

Figure 3. Odds ratios by the decile of polygenic risk score estimated based the top SNPs within the ten Caucasian-specific loci.

The polygenic risk score (PRS) was calculated based on the ten Caucasian-specific SNPs as described (online Methods). The PRS were converted to deciles (1=lowest, 10=highest RPS), and nine dummy variables created to contrast deciles 2–10 to decile 1 as the reference. Odds ratios and 95% confidence intervals (error bars) were estimated using logistic regression with principal components to control for population stratification.

Figure 4. The regional association plots of IL23R showing allelic heterogeneity.

The relative location of annotated genes and the direction of transcription are shown in the lower portion of the figure, and the chromosomal position is shown on the x axis. The blue line shows the recombination rate (estimated from HapMap data of CEU, CHB and Combined population) across the region (right y axis), and the left y axis shows the significance of the SNP associations (−log10 P). The square indicates the SNPs for conditional analysis (these are the top or secondary SNPs); the circle labelled with rs IDs are reported psoriasis susceptibility SNPs. All circles and squares are colour filled based on the heterogeneity results (I²) in our trans-ethnic meta analysis. (a,b) Unconditional and conditional logistic association results of Caucasian, (c, d) unconditional and conditional logistic association results of Chinese.

Figure 5. The regional association plots of IL28RA shared locus without heterogeneity.

The relative location of annotated genes and the direction of transcription are shown in the lower portion of the figure, and the chromosomal position is shown on the x axis. The blue line shows the recombination rate (estimated from HapMap data of CEU, CHB and combined population) across the region (right y axis), and the left y axis shows the significance of the SNP associations (−log10 P). The square indicates the SNPs for conditional analysis (these are the top or secondary SNPs); the circle labelled with rs IDs are reported psoriasis susceptibility SNPs. All circles and squares are colour filled based on the heterogeneity results (I²) in our trans-ethnic meta analysis. (a,b) Unconditional and conditional logistic association results of Caucasian, (c,d) unconditional and conditional logistic association results of Chinese, (e,f) unconditional and conditional logistic association results of trans-ancestry combined sample.