Evidence for a causal association between psoriasis and psychiatric disorders using a bidirectional Mendelian randomization analysis in up to 902,341 individuals

Psoriasis is a chronic, inflammatory, disabling, and disfiguring skin disease with a prevalence of 0.09–11.43 %, which is also increasing year by year, affecting about 2 % of the world's population. It is mainly characterized by scaly patches on the skin with pain and itching, which brings huge physical, psychological, and social burdens to patients. Its pathogenesis is related to a variety of genetic and environmental factors (Griffiths et al., 2021; Walter, 2022; World Health Organization, 2016). Psoriasis is a complicated genetic disorder. Large cohort studies of twins have shown that identical twins have a higher prevalence of psoriasis than heterozygous twins and that 60–70 % of the variations in susceptibility to psoriasis can be explained by genetic factors (Lonnberg et al., 2013). A recent meta-analysis on genome-wide association studies (GWAS) showed that 63 loci, including IL23R, IL12B, IL23A, and TRAF3IP2, were involved in the development of psoriasis (Tsoi et al., 2017). Environmental factors, such as stress, smoking, alcohol abuse, and obesity, can also contribute to the development of psoriasis. At present, it is believed that the immune system plays a major role in the development of psoriasis. Among all the types of classical immune cells deemed responsible for pathogenesis, T cells are recognized as the main players. Studies have shown that immune responses, especially T cell-mediated immune-inflammatory responses such as the IL23/IL17 axis, are involved in the development of many systemic chronic diseases such as cardiovascular diseases, diabetes mellitus, and mental diseases (Lowes et al., 2014). Meanwhile, psoriasis accompanied by type II diabetes mellitus, cardiovascular diseases, and mental diseases (especially depression) has been extensively reported and studied, indicating that there might be common pathways of psoriasis and its comorbidities (Yamazaki, 2021).

To date, many studies have suggested that there is a positive association between psoriasis and mental illnesses. The prevalence of depression and anxiety disorder in patients with psoriasis (20–50 %) was found to be 1.5 times higher than that in the general population, and schizophrenia and suicidal ideation were found more common in patients with psoriasis (Hedemann et al., 2022; Parisi et al., 2019). However, there are few epidemiological studies on bipolar disorder in patients with psoriasis. In some cohort studies adjusted for confounders, psoriasis was associated with 23 % increased risk of developing depression, 32 % increased risk of developing anxiety, and 55 % increased risk of developing bipolar disorder (Kimball et al., 2012). Some studies even found a bidirectional relationship between psoriasis and psychiatric disorders such as depression (Lowes et al., 2014): patients with psoriasis were more likely to develop psychological diseases, while mental illnesses could exacerbate psoriasis (Tohid et al., 2016). A large GWAS showed that psychiatric disorders were closely associated with the genetic loci related to the immune system (C. Schizophrenia Working Group of the psychiatric genomics, 2014). Some other meta-studies showed that the risk of psoriasis increased 1.83 times in patients with schizophrenia, as compared with normal controls, and mental stress became a recognized predisposing factor for psoriasis (Ungprasert et al., 2018). Despite the findings on the relationship between psoriasis and psychiatric disorders, the studies were still affected by common confounders (e.g., smoking, alcohol abuse, socioeconomic ability) and showed discrepancies due to different classification criteria and the great heterogeneity.

Considering the limitations of traditional observational studies, the causal relationship between psoriasis and psychiatric diseases is still unclear due to a variety of confounding factors and biases; such confounding factors and biases may even lead to the finding of reverse causality (Smith et al., 2007). Mendelian randomization (MR) is a statistical method that uses SNP to simulate randomized controlled trials (RCTs). It aims to observe and investigate the causal relationship between exposure and outcome variables in epidemiology based on eliminating interferences of confounding factors and, using genetic variations as IVs, to analyze the relationship between diseases. As the chromosomes with genetic variations are fixed and randomly assigned during meiosis with no disturbance of environmental factors, the internal relationship between them can be inferred. Thus, this study aims to explore the causal relationship between psoriasis and a series of psychiatric disorders with the use of bidirectional MR analysis (Fig. 1).

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