Genome-wide meta-analysis and integrative fine-mapping identify novel susceptibility loci and effector genes in psoriatic arthritis

Abstract

Psoriatic arthritis (PsA) is a complex immune-mediated inflammatory disorder affecting both the skin and musculoskeletal system. Although genome-wide association studies (GWAS) have identified multiple loci shared with psoriasis (PsO), the unique genetic architecture of PsA remains incompletely understood. To define PsA-specific genetic risk, we conducted a GWAS meta-analysis of 13,512 PsA cases and 715,639 non-PsA population controls, identifying 40 susceptibility loci, including 21 novel loci outside the MHC region. These include putative coding variants in genes such as DENND1B, as well as non-coding variants implicating new therapeutic targets. We applied expression quantitative trait loci (eQTL)-based post-GWAS analyses to prioritize high-confidence candidate genes at both novel (e.g., PRR5L) and established loci. To further resolve cellular context, we curated and re-analyzed a comprehensive, cell type-resolved eQTL resource, enabling downstream single-cell analyses that identified disease-relevant NADK-positive monocyte subsets and implicated candidate genes such as ETS1. Finally, we uncovered PsA-specific genetic signals within PsO GWAS loci, including a previously unrecognized association at C1orf14 within the IL23R region. Our findings underscore the importance of large-scale genetic studies combined with fine phenotypic resolution to disentangle shared and disease-specific genetic mechanisms in PsA.