Unsaturated fatty acids mediate the bidirectional link between psoriasis and depression: Evidence from observational and mendelian randomization studies.

BACKGROUND

Depression is a prevalent and debilitating comorbidity of psoriasis. While the epidemiological association between the two conditions is well established, the causal relationship and the underlying biological mechanisms remain insufficiently understood.

OBJECTIVES

To evaluate the causal association between psoriasis and depression, as well as the mediating function of circulating unsaturated fatty acids (UFAs).

METHODS

We combined cross-sectional analysis of 211 psoriasis patients, high-throughput serum metabolomics, and bidirectional Mendelian randomization (MR) using large-scale genome-wide association studies (9267 psoriasis cases; 170,756 depression cases). Multivariable MR analyses were adjusted for body mass index (BMI) and smoking. Two-step MR mediation was used to assess the role of UFA phenotypes.

RESULTS

Clinically significant depressive symptoms (PHQ-9 ≥ 10) were present in 32.7% of patients and were independently associated with higher BMI, smoking, special site involvement, and higher PASI scores. MR analyses indicated a robust bidirectional causal relationship between psoriasis and depression, independent of BMI and smoking. Serum metabolomics revealed reduced omega-3 PUFAs (DHA, DPA, ETA) and elevated MUFAs in psoriasis patients with depression. Mediation MR identified the DHA-to-total fatty acid ratio as a key causal intermediary from psoriasis to depression, whereas depression liability altered PUFA/MUFA ratios to promote psoriasis risk.

CONCLUSIONS

Our integrative approach reveals a causal, bidirectional link between psoriasis and depression and indicates that unsaturated fatty acid imbalance, particularly reduced omega-3 PUFAs, may serve as a potential mediating mechanism. These findings highlight modifiable intervention targets, including weight management, smoking cessation, and omega-3 supplementation, may help to simultaneously improve dermatologic and psychiatric outcomes.