Association between schizophrenia and psoriasis: A two‐sample bidirectional Mendelian randomization study

Observational studies have showed an association between schizophrenia and risk of psoriasis and vice versa. However, whether schizophrenia is causally associated with psoriasis is unclear.

Until now, few observational epidemiological studies revealed that people with schizophrenia have an increased risk of psoriasis and vice versa. 11,12The association between schizophrenia and psoriasis has been in dispute.Psoriasis has been identified in a metaanalysis with six observational studies as a risk factor for patients with schizophrenia, while the other meta-analysis with five studies also found that patients with schizophrenia had increased incidence of psoriasis.Recent genetic data also supports that there is a shared genetic etiology between schizophrenia and psoriasis. 13However, it remains unclear whether there is a bidirectional interaction and causation relationship between schizophrenia and psoriasis, due to the existence of confounders and reverse causality in observational studies. 14ndelian randomization (MR) analysis is an novel epidemiological approach that uses genetic variants (i.e., single nucleotide polymorphisms, SNPs) as instrumental variables (IVs) to analyze the causal link between exposures and outcomes, 15 which could avoid latent confounding factors and reverse causation.MR analysis therefore has the ability to examine the exposure-outcome causal relationship in a robust manner.
In this study, a two-sample bidirectional MR analysis was used to investigate the potential causation between schizophrenia and psoriasis.

| Study design
A two-sample bidirectional MR analysis mode is designed in this study to examine the causal association between schizophrenia and psoriasis (Figure 1).MR analyses are required to obey the following assumptions.
First, the IVs should be significantly correlated with the exposure.
Second, the IVs should be independent.Lastly, the IVs should have no effect on the outcome except through exposure.

| Data sources
Schizophrenia summary statistics were derived from the Psychiatric Genomics Consortium (PGC) genome-wide association study (GWAS) study, which consisted of 33 640 cases and 43 456 controls.
108 independent, genome-wide SNPs that have been shown to be significantly (p = 5 × 10 −8 ) related to schizophrenia were identified and used for our analysis.The summary statistics are accessible with the GWAS ID "ieu-b-42" in the IEU OpenGWAS project database (https:// gwas.mrcieu.ac.uk/ ).Psoriasis summary statistics were obtained from the UK Biobank GWAS study (ukb-b-10 537), which included 5314 cases and 457 619 controls.The UK Biobank is a prospective research that collected genome-wide genotype data on around 500 000 people from all over the UK and obtained a wealth of phenotypic and health-related data. 16The summary statistics are accessible at http:// www.neale lab.is/ uk-bioba nk/ .Furthermore, to reduce potential bias due to population heterogeneity, all SNPs in the MR analysis were drawn from a GWAS of European ancestry.Because the data used in this case was publicly available in the database, no further ethical approval was required.
The brief information is shown in Table 1 and the details are presented in Table S1.

| Selection of IVs
SNPs that met genome-wide significance (p < 5 × 10 −8 ) were selected from the GWAS summary statistics of schizophrenia and psoriasis, respectively.To assure independence and rule out the effect of linkage disequilibrium, SNPs need to be extracted using the PLINK clumping method with a strict clumping threshold (linkage disequilibrium parameter r 2 < 0.001, distance kb = 10 000).Then all palindromic SNPs that could cause ambiguity to the identity of the effector allele were excluded and the directions of the effects of SNPs were harmonized.In addition, R 2 and F statistic values were calculated to evaluate these IVs, in order to assess their correlation with exposure and limit bias from weak IVs relevance; that is, F > 10 means sufficient for MR analysis. 17,18

| MR analyses
In our two-sample MR analysis, the inverse-variance weighted (IVW) analysis was selected as the primary method to valuate the causal effects of schizophrenia on psoriasis outcomes and vice versa. 19The IVW method is based on the validity of each IV according to the MR assumptions and used a meta-analytic approach to aggregate Wald F I G U R E 1 Diagram for key assumptions of Mendelian randomization (MR) analyses.
estimates for each IV to produce a robust evaluation of the causal relationship of the exposure on the outcome. 19We estimated the odds ratio (OR) with 95% confidence interval (CI) and produced the SNP effect scatter plot.We also used two additional MR analyses: the MR-Egger 20 and weighted median test, 21 both of which provide more robust results in a broader set of scenarios, despite being less efficient (wider CIs).

| Sensitivity analyses
Sensitivity analyses were performed to assess the robustness of the results, including pleiotropy, heterogeneity, leave-one-out tests, funnel plots, and MR-Steiger filtering.MR-PRESSO approach was used to identify and correct potential outliers, 22 and evaluate the potential pleiotropy.p-value of the MR-Egger intercept was used to determine the direction of multiplicity and make corrections.Cochrane's Q-value was used to evaluate the heterogeneity; the fixed-effect model was used if no heterogeneity was observed (p < 0.05); otherwise, a random-effect model was applied. 23In addition, leave-one-out test was used to determine whether a single SNP had a significant independent influence on the MR estimation.
A funnel plot was used to assess the probable directional pleiotropy, in which symmetric graphics indicated the absence of pleiotropy. 24-Steiger filtering was performed to remove SNPs that implied a reverse causal direction. 25R software (TwoSampleMR package and MRPRESSO package) was used to perform MR analyses.p < 0.05 was considered statistically significant.

| Causal effect of schizophrenia on psoriasis
After the screening, a total of 81 independent SNPs related to schizophrenia were identified and listed in Table S1.IVW analysis revealed that schizophrenia was associated with an increased risk of psoriasis [OR: 1.001, 95% CI: 1.000-1.002,p = 0.012].Weighted median (OR: 1.001, 95%CI: 1.001-1.003,p = 0.002) and MR-Egger method (OR: 1.003, 95%CI: 1.000-1.007,p = 0.038) both showed a consistent result (Table 2) and scatter plot of SNP effect of schizophrenia on psoriasis was shown in Figure 2A.
There was no evidence of heterogeneity among individual SNPs according to Cochran's Q-test (p > 0.05).The MR-Egger intercept test and the MR-PRESSO global test proved no horizontal pleiotropy.Leave-one-out sensitivity analysis showed that results were not driven by any single SNP, and the funnel plots were symmetrical (Table 3, Figures 3A and 4A).

| Causal effect of psoriasis on schizophrenia
After the screening, a total of 21 independent SNPs in association with psoriasis were obtained and listed in Table S2.In the MR-PRESSO analysis, two outliers were found and eliminated.IVW analysis indicated that there was no causal effect of genetically predicted psoriasis on schizophrenia (OR: 0.221, 95%CI: 0.029-1.682,p = 0.145).Weighted median (OR: 0.134, 95%CI: 0.018-1.010,p = 0.051) and MR-Egger method (OR: 0.121, 95%CI: 0.009-1.586,p = 0.126) were performed as the complement to IVW and confirmed the consistent results (Table 2).A scatter plot of SNP effect of psoriasis on schizophrenia was shown in Figure 2B.Sensitivity analyses also revealed consistent results, indicating the robustness of the results and suggesting that psoriasis has no causal effects on schizophrenia (Table 3; Figures 3B and 4B).

| DISCUSS ION
This is the first study to evaluate the bidirectional causal relationship between schizophrenia and psoriasis by performing a two-sample MR approach.We found that there is a causal link between schizophrenia and psoriasis, and the genetically predicted schizophrenia was associated with an increased risk of psoriasis in European population.However, no evidence of genetically prediction for psoriasis and schizophrenia was observed in the reverse MR analysis.
Multiple sensitivity analyses were performed to further confirm the results.
The relationship between schizophrenia and psoriasis has been discussed for decades, with the latest results comprising two metaanalyses.One meta-analysis of six observational studies, with around 6.1 million individuals found that patients with schizophrenia had a 1.83-fold increased incidence of psoriasis in comparison with controls. 26The other meta-analysis analyzed five studies with more than six million patients, revealing that psoriasis increased the risk of schizophrenia (OR: 1.41; 95%CI: 1.19-1.66). 27Although cumulative evidences from observational studies showed a correlation between psoriasis and schizophrenia risk, observational research is prone to being influenced by confounders, thereby affecting exposure and results, which makes it challenging to draw accurate causal conclusions.Furthermore, it is still uncertain if the observational correlation denotes a causal relationship.In this regard, a MR method was carried out to reveal the potential causal relationship of schizophrenia on psoriasis.
Although the underlying pathophysiology of schizophrenia and psoriasis has not been fully understood, shared genetic factors and immunological pathways suggest a potential overlap in their pathogenesis. 13,28The association between the two diseases could be explained by few possible interpretations, likely involvement of shared genetic factors and immunologic mechanisms.Chromosomes 6p21.3 29 and 6p21.1 30 are related with psoriasis and schizophrenia respectively.The simultaneous transfer of these two susceptible genes could be caused by these two neighboring chromosomes.Moreover, SNP variants of the human leukocyte antigen gene on chromosome 6 have been detected, implying that calcium signaling may also take part in the progression of these two diseases. 13It is hypothesized that helper T cells (Th17) contribute significantly to the onset and growth of central nervous system (CNS) inflammation, and further CNS inflammation may have an important role in the onset and development of schizophrenia according to the mild encephalitis hypothesis. 31,32 addition, Th17 cells and TNFα also significantly contribute to the development of psoriasis. 33Thus, evidence suggests that the immune dysregulation of Th17 could be the common underlying cause of both diseases and further research will be needed to assess more targeted treatment, for example, whether biologic agents targeting Th17 signaling could be a treatment plan in patients with schizophrenia.

| Limitation
There are some limitations in this study.First, our study only included European ancestry samples, which minimized the bias of demographics but limits the universality to other populations.
Additional data collecting and analysis will be required to evaluate whether the findings apply to other populations.Second, although sensitivity analyses supported the primary findings, horizontal pleiotropy cannot be entirely ruled out. 20Nonetheless, the sensitivity  analyses indicated that it was unlikely that horizontal pleiotropy would affect our findings.Lastly, due to the lack of detailed clinical information, we were unable to conduct a subgroup analysis; therefore, more studies will be required to confirm our findings.

| CON CLUS ION
In conclusion, our study provides new evidence for the causal relationship between schizophrenia and psoriasis; the genetically

F I G U R E 2
Scatter plots of Mendelian randomization (MR) analysis.(A) Schizophrenia on psoriasis; (B) psoriasis on schizophrenia.TA B L E 3 Sensitivity analysis of the causal association between schizophrenia and psoriasis.

F I G U R E 3
Leave-one-out sensitivity analysis.(A) Schizophrenia on psoriasis; (B) psoriasis on schizophrenia.predicted schizophrenia increased the risk of psoriasis.Awareness should be raised among clinicians about the potential risk of psoriasis in patients with schizophrenia, which helps with systematic diagnosis and early interdisciplinary and customized treatment of patients.That is, clinicians should be alert to suspicious skin disease symptoms in individuals with schizophrenia and early intervention and therapies are beneficial to improve prognosis in patients with psoriasis secondary to schizophrenia.Further research should be conducted on the pathophysiologic mechanisms affecting the development of psoriasis in patients with schizophrenia.