Dissection of shared genetic architecture and biological association between psoriasis and cardiovascular disease based on genome-wide association studies.

Abstract

Background: The clinical link between psoriasis (PsO) and cardiovascular diseases (CVDs) is well-established, yet the genetic underpinnings of their comorbidity remain unclear. This study aimed to systematically map the shared genetic architecture between PsO and CVDs to identify key risk loci, effector genes, and biological pathways.

Methods: We analyzed large-scale genome-wide association study data for PsO and 11 CVDs to assess their genetic correlation. We then identified pleiotropic loci-variants associated with both PsO and CVDs-and applied colocalization analysis to test whether a single causal variant at each locus could explain the shared association. To interpret these findings, we performed functional annotation to map variants to genes and conducted heritability enrichment analysis to identify critical tissues. Finally, we performed an immune-specific colocalization analysis to investigate the role of distinct immune cell types in driving the shared disease risk.

Results: The findings revealed significant shared genetic risk between PsO and seven major CVDs (e.g., hypertension, myocardial infarction, and coronary artery disease). We identified 58 pleiotropic loci at the level of genome-wide significance (P < 5 × 10^-8). Of these, 11 loci passed causal colocalization tests, indicating a high probability of a shared causal variant. Gene-level analysis pinpointed 97 candidate genes, and through multi-evidence integration, we prioritized four (SLC22A5, LMAN2, HSD3B7, and ZNF668) as high-confidence therapeutic targets. Enrichment analyses showed these shared genes are highly expressed in blood and immune-related tissues and are involved in key pathways such as immune activation and cytokine signaling. Furthermore, our findings suggest that T-cell-mediated immune dysregulation is a key mechanism underlying the comorbidity of PsO and at least five of the studied CVDs.

Conclusion: Our systematic genetic analysis identifies shared loci and candidate genes for psoriasis and several cardiovascular diseases. The findings point toward immune-mediated pathways as potential links between these conditions and provide a prioritized list of targets warranting future functional study and therapeutic evaluation.