Association between psychiatric hospitalizations of patients with schizophrenia and polygenic risk scores based on genes with altered expression by antipsychotics.

Objective: To test whether a schizophrenia polygenic risk score (PRS) based on the subset of polymorphisms that affect brain expression of genes with altered expression by antipsychotics (exprAP PRS) is associated with psychiatric readmission of patients with schizophrenia.

Methods: The study involved 427 patients with schizophrenia. Genes with altered expression by antipsychotics were extracted from the Comparative Toxigenomics Database. ExprAP PRS was estimated using the clumping and thresholding (p < 0.05) method. Two additional PRS were tested based on subsets of exprAP polymorphisms whose schizophrenia risk allele has the same (unrestored PRS) or opposite (restored PRS) direction of effect on gene expression than antipsychotics. A general SCZ PRS was tested for comparison. Logistic and ordinal regression were used to test for association of each PRS with ever readmission and admission history, an outcome based on length and number of admissions, respectively. Webgestalt was used for Gene Ontology enrichment analysis.

Results: ExprAP PRS was associated with ever readmission (OR = 1.48, 95%CI:1.10-1.97) and admission history (OR = 1.30, 95%CI 1.07-1.57). SCZ PRS (OR = 1.22, 95%CI: 1.01-1.48) and unrestored PRS (OR = 1.26, 95%CI 1.04-1.53) were only associated with admission history. Genes at exprAP PRS were enriched in regulation of cytokine production.

Conclusion: Our findings suggest that PRS based on genes with altered expression by antipsychotics may be better predictors of readmission than SCZ PRS, warranting further investigation in larger cohorts of patients. The action of antipsychotics may be related to brain gene expression, mainly in genes involved in immunity.