Genetic Evidence Supports a Causal Link Between Psoriasis and Depression

A new Mendelian randomization (MR) study adds clarity to a long-debated question in dermatology and behavioral medicine: does psoriasis predispose patients to depression? Drawing on large genome-wide association study (GWAS) datasets from European populations, the investigators report that genetic susceptibility to psoriasis increases the likelihood of depression by roughly one-third (OR: 1.348, 95% CI: 1.141–1.592; P =.004).¹

The effect persisted across robustness checks and held its direction when the researchers tested for reverse causality, pointing toward a true causal relationship rather than shared circumstances or disease burden, study authors asserted.¹

The findings, published in the International Journal of Clinical Practice, reinforce what clinicians often see in practice, ie, individuals with psoriasis who struggle with mood symptoms even when their skin disease appears well controlled. By anchoring the association in inherited risk, the study offers new evidence that psoriasis and depression may intersect far earlier than clinical onset, likely through shared immunologic pathways.¹

Looking for Genetic Underpinnings

The authors, from the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China, position their study in the context of decades of observational research documenting higher rates of depressive symptoms, major depressive disorder, and suicidality among people with psoriasis.^2,3 These studies consistently show elevated risk, particularly in severe disease, yet they cannot fully resolve why the conditions cluster. Psychosocial burden, flare-related stress, systemic inflammation, and comorbid conditions may all influence mood outcomes. At the same time, depression and stress reactivity have appeared as potential risk factors for developing psoriasis. Disentangling directionality, therefore, has remained difficult.^2,3

According to the investigators, Mendelian randomization (MR) provides an approach suited to that challenge. Because genetic variants are fixed at conception and not shaped by life experiences or disease progression, they bypass many of the confounders that limit observational research. If psoriasis-associated genetic variants also increase risk for depression, and the association consistently flows in that direction, the case for a causal relationship strengthens.¹

Study Design and Key Findings

The investigators used GWAS summary statistics from 3871 psoriasis cases and more than 333,000 controls in the UK Biobank, paired with an independent dataset of more than 113,000 depression cases. Thirteen genomewide-significant single nucleotide polymorphisms (SNPs) served as instrumental variables after meeting criteria for strength, independence, and absence of known confounding.

Across the primary and supporting MR analyses, genetic predisposition to psoriasis increased depression risk by approximately 30% to 35%. No single SNP altered the estimate, and no evidence emerged of heterogeneity or bias driven by alternative biological pathways, according to the study.

Genetic predisposition to psoriasis increased depression risk by approximately 30% to 35%.

A key finding came from colocalization analysis, which identified rs12189871 (located near HLA-C and HLA-B) as a shared causal signal. Expression data from GTEx showed its regulatory effects on HLA-region genes across multiple tissues. Because these loci shape CD8+ T-cell activation, cytokine production, and inflammatory signaling, they provide a plausible biological bridge between psoriatic inflammation and neural processes relevant to mood regulation.

Results in Context

The genetic signal identified in this study provides structure to a set of clinical observations that have long suggested a bidirectional interplay between inflammation and mood. Many individuals with psoriasis report emotional and physiologic stress that appears to heighten symptom perception or precede disease flares. Depression, in turn, has been associated with more variable clinical response to treatment.^4,5 Epidemiologic studies have also hinted that stress-related pathways may raise the risk of developing psoriasis.^4,5 The new MR evidence reframes these observations by suggesting that underlying genetic architecture—rather than downstream disease burden—may help set the stage for both conditions to emerge.

The new MR evidence reframes these observations by suggesting that underlying genetic architecture, rather than downstream disease burden, may help set the stage for both conditions to emerge.

Among the study's limitations that could temper interpretation of the findings the investigators acknowledge the single source of GWAS data, derived only from individuals of European ancestry. And, while the investigators observed no evidence of horizontal pleiotropy, undetected pleiotropic pathways remain possible. The functional significance of rs12189871 and its related genes requires experimental validation. In addition, the analysis treats depression as a broad phenotype, preventing evaluation of differential risk across depressive subtypes.

"This fnding has important clinical implications, underscoring the necessity for dermatologists and primary care physicians to integrate routine depression screening and management into the standard care of patients with PSO," study authors wrote. They add that an integrated approach "could lead to earlier detection, improved mental health outcomes, and potentially better overall management of the skin condition."¹

The research team highlighted several priorities for future work: clarifying how HLA-linked inflammatory pathways influence neural circuits involved in mood; extending analyses to non-European populations; and examining whether effective depression treatment may alter psoriasis trajectory.¹

References

1. Guo B, Bai Y, Yang Y, et al. Genetic susceptibility to psoriasis increases risk of depression: evidence from a Mendelian randomization study. Int J Clin Pract. Published online December 9, 2025. doi:10.1155/ijcp/9238266

2. Singh S, Taylor C, Kornmehl H, Armstrong AW. Psoriasis and suicidality: a systematic review and meta-analysis. J Am Acad Dermatol. 2017;77(3):425-440. doi:10.1016/j.jaad.2017.05.019

3. Kurd SK, Troxel AB, Crits-Christoph P, et al. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146(8):891-895. doi:10.1001/archdermatol.2010.186

4. Dalgard FJ, Gieler U, Tomas-Aragones L, et al. The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries. J Invest Dermatol. 2015;135(4):984-991. doi:10.1038/jid.2014.530

5. Dowlatshahi EA, Wakkee M, Arends LR, Nijsten T. The prevalence and odds of depressive symptoms and clinical depression in psoriasis patients: a systematic review and meta-analysis. J Invest Dermatol. 2014;134(6):1542-1551. doi:10.1038/jid.2013.508