Integration of GWAS and single-cell analysis for psoriasis identifies disease-associated cell subtypes and therapeutic targets

Abstract

Psoriasis is a heritable, common chronic autoimmune disorder characterized by cycles of remission and flare-ups. Here, we jointly analyze genomic and single-cell transcriptomic data to elucidate the genetic and molecular architecture of psoriasis. We perform a large-scale genome-wide meta-analysis of individuals of European ancestry (n = 1,131,685) and identify 125 independent susceptibility loci associated with psoriasis, including 17 previously unreported loci. Integrating these findings with single-cell transcriptome data identifies the predominant roles of myeloid and T cells in psoriasis and the enriched expression of disease-associated genes in keratinocytes and endothelial cell subsets. Finally, we prioritize 50 potential therapeutic target genes using multiple robust approaches and identify their cell subtype-specific activity patterns across non-lesional, lesional, and treatment conditions, thereby revealing layer-specific cross-cell-type interactions in psoriasis. These findings provide perspectives regarding the pathogenesis of psoriasis and highlight the role of immunometabolism in disease progression. Integrating genetic data and skin single-cell data highlights psoriasis-associated cell types and cell type-specific functional mechanisms. These findings offer perspectives for identifying therapeutic targets for psoriasis at the cellular level.