Uncovering Cell-Type Heterogeneity Identifies LRRC25 as a Putative Shared Immunoregulatory Candidate for Psoriasis and Periodontitis

Introduction Psoriasis is a chronic immune-mediated inflammatory skin disease with a complex genetic background, susceptible to psoriatic arthritis as a complication. However, interpretation of genetic associations from bulk tissue analyses is limited by cellular heterogeneity, hindering mechanistic inference. This study aimed to explore cell-type-specific causal regulatory mechanisms between psoriasis and periodontitis. Methods We integrated psoriasis and periodontitis genome-wide association data with three single-cell expression quantitative trait locus (sc-eQTL) datasets (OneK1K, sc-eQTLGen, and dynamic CD4+ T-cell activation). Two-sample Mendelian randomization (MR) was supplemented by bulk eQTL, plasma protein QTL, and Steiger directionality analyses. Prioritized genes were further examined using single-cell transcriptomics, network-based in silico perturbation, functional enrichment, drug-signature analysis, and molecular docking. Results Cell-type-resolved MR analyses revealed heterogeneous and context-dependent genetic effects across immune cell subsets, with both concordant and discordant associations between psoriasis and periodontitis. Among the prioritised candidates, LRRC25 showed nominally significant MR associations with both diseases, although these associations were not corrected for multiple testing. Bulk blood-derived eQTL analyses showed consistent inverse associations with both diseases, whereas naive B cell-specific MR analyses showed associations in the opposite direction. Single-cell RNA sequencing showed that LRRC25 expression was predominantly detected in monocytes, whereas only a small proportion of naive B cells expressed LRRC25 . In silico LRRC25 perturbation in monocytes produced concordant transcriptional changes across psoriasis and periodontitis, with FCGR3A identified as a central network hub. Functional enrichment analyses implicated innate immune, type I interferon and Fc receptor-related pathways. Conclusions LRRC25 emerged as a putative shared immunoregulatory candidate, although evidence varied across molecular levels and immune cell contexts. No statistically significant shared protein-level association was identified. Our findings suggest that bulk eQTL inference may obscure cell-type-specific regulatory signals and highlight the value of single-cell-informed gene prioritization. Further experimental validation is needed.