GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets

Abstract

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Figure 1 –. Manhattan plot summarising genome-wide associations with psoriasis susceptibility

x-axis, genomic position; y-axis, −log₁₀(P-value) of association; red and green points, regions previously and newly associated, respectively, with psoriasis susceptibility at genome-wide significance (P=5×10⁻⁸) in European ancestry populations; solid horizontal line, genome-wide significance threshold; dotted horizontal line, y-axis break at 10⁻³⁰; chromosomes (labelled 1–22) are alternately shaded for clarity.

Figure 2 –. Statistical and functional fine-mapping

A. Comparison of 95% Bayesian credible sets to previous GWAS meta-analysis. Each point represents a different association signal established in the previous meta-analysis (Tsoi et al., 2017). Point colour indicates direction of change, blue dashed line indicates equality. B. Prioritisation of protein-altering variants. Points represent protein-altering variants identified in Bayesian credible sets for independent psoriasis signals; x-axis: posterior probability of causality from statistical fine-mapping analysis, y-axis: CADD score estimating deleteriousness of protein altering variant, point colour: whether corresponding susceptibility signal is in a known or newly reported genomic region and whether primary or secondary signal. Note the TRAF3IP2 variant is rs33980500, discussed in the main text. C. Highlighted high-confidence regulatory variants derived from TURF analysis. For each variant, bars show the generic and tissue-specific regulatory probabilities (y-axis) estimated by TURF for all tissues (x-axis). Blood and skin are highlighted in orange and blue, respectively.

Figure 3 –. Relative expression of TWAS genes in single-cell skin transcriptomes of psoriasis patients

Expression level (cell colour; purple-red scale) represents mean value among cells in the corresponding cell type/condition (x-axis). For each gene (y-axis), the values were standardised and expression patterns were used for clustering (dendrogram, left hand side). Five clusters were identified (grey/black bars, left hand side) and labelled according to the cell types that exhibit highest expression for the genes in the cluster. PP, psoriasis lesions; PN, non-lesional skin; Lymph Endo, lymphatic endothelial cells; IFE, interfollicular epidermis. Clusters are identified based on enrichment for: (1) lymphatic endothelial and eccrine cells; (2) keratinocytes; (3) T cells and dendritic cells; (4) melanocytes; (5) fibroblasts, lymphatic endothelial cells and pericytes.