176 Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine-mapping in the MHC and genomewide

Abstract

We performed a GWAS of psoriasis in 2,590 cases and 1,720 controls of South Asian descent (SAS). Compared to our existing European-origin (EUR) GWAS, the effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman r = 0.78; p < 2 x 10−14). We then conducted a transethnic meta-analysis, identifying two novel non-MHC psoriasis loci (1p36.22 and 1q24.2). rs2103876 (1p36.22) is a cis-eQTL in blood for MTHFR, whose expression is positively correlated (p=4.2x10−97) with the psoriasis risk allele (T) and overexpressed in psoriatic lesional (PP) skin (p=3.06x10−23; FC =1.7). The only significant blood eQTL target for rs12046909 (1q24.2) is XCL1, a chemokine receptor ligand that is also overexpressed in PP skin (p=0.011; FC=1.95). For these two loci, the transethnic GWAS provided higher genetic resolution (mean reduction in 95% CI= 20 kb) and a reduction in the number of potential causal variants (mean = 10) than EUR alone. We explored multiple strategies to develop reference panels for accurately imputing MHC genotypes in both SAS and EUR. HLA-C*06 was the top-ranking MHC locus in both populations but was even more prominent in SAS. Transethnic modeling also substantially boosted the probability that HLA-C*06 is causal. Analysis of the extended MHC region uncovered 5 independent psoriasis loci in SAS, 14 in EUR, and 17 in transethnic, all of which map to the classical MHC. Secondary MHC signals included coding variants of HLA-C and HLA-B, but also potential regulatory variants of these two genes as well as HLA-A and several HLA class II genes, with effects on both chromatin accessibility and gene expression. This study highlights the value of transethnic meta-analysis for discovery and fine-mapping of susceptibility loci.