Exploring Causal Relationships of Depression and Psoriatic Disease (Psoriatic Arthritis and Psoriasis) Through Mendelian Randomization

Objectives Previous observational studies have demonstrated an association between PsA and depression (comorbidity). However, whether these associations are causative and reverse causality was not assessed. Mendelian randomization (MR) can assess causality between exposure and an outcome by using genetic instrumental variables. In this study, we perform a bidirectional two-sample MR to explore the complex causal relationship between depression and PsA or psoriasis. Methods The study cohorts (depression, PsA, psoriasis and controls) were identified from the UK or FinnGen biobank. The summary statistics from Genome-wide association studies (GWAS) were extracted from IEU GWAS database. The selection of SNPs was performed by considering the GWAS significance(5e-07), clumping, linkage disequilibrium, and minor allele frequency. The effects alleles were harmonized for exposures and outcomes. Heterogeneity and horizontal pleiotropy analysis were also performed. An inverse variance weighted (IVW) model was used to estimate causality for each IV in this two-sample MR study. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for causal estimations. The MR also was performed in both directions to explore the possibility of reverse causality. Results Patients with depression (170,756), PsA (1553), psoriasis (4510) and controls (147211 to 329433) were analyzed. The number of instrumental variables (SNPs) is presented in Table 1. Although there appeared to be a positive association between depression and PsA and psoriasis, it did not reach statistical significance (OR 1.19, 95% CI 0.87-1.64, p = 0.27) for PsA but a significant causal effect (OR 1.3 (1.08-1.58), p=0.006) for psoriasis. There was no evidence for reverse causation of psoriasis leading to depression (OR 1.0 (0.98-1.02), p=0.82) and significance for reverse causation of PsA leading to depression was significant (OR 1.02 (1.0-1.03), p=0.002). Table 1 Conclusion This study underscores the importance of MR as a powerful tool for establishing causal relationships in rheumatology, which has significant implications for clinical practice. The lack of a significant consistent causal link between depression and PsA suggests that the relationship observed in observational studies may be due to confounding factors and potential bias, however, there appears to be a causal association of depression leading to psoriasis.

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