Association of schizophrenia polygenic risk scores with treatment-resistant schizophrenia

A significant proportion of schizophrenia patients continue to suffer from psychotic symptoms even after being prescribed at least two antipsychotic medications. They are regarded as being treatment-resistant, and are often treated with clozapine. Studies have attempted to examine the genetic factors underlying treatment resistance, with most recent studies reporting associations between treatment resistance and polygenic risk score (SCZ-PRS) for schizophrenia based on summary statistics from an earlier genome-wide association study (GWAS). We performed polygenic risk score analysis of treatment resistance using the latest (Phase 3) schizophrenia GWAS summary statistics in our sample of 156 patients of European ancestry with DSM-IV diagnosis of schizophrenia or schizoaffective disorder. We calculated standardized SCZ-PRS from summary statistics of the latest schizophrenia GWAS (leave-one-out; Trubetskoy et al, 2022) using the PRS-CS-auto method. We analyzed the effect of SCZ-PRS on risk of treatment resistance (based on clozapine use status) in a logistic regression model, with sex, age, and the first two population principal components as covariates. We found SCZ-PRS to be significantly associated with treatment resistance status (beta=0.54, SE=0.21, p=0.012). Patients with top 10% of SCZ-PRS are 4.76 times as likely to be treatment resistant as patients in the other patients (p=0.006), controlling for covariates. Our findings provide support for the potential use of the genetic risk scores for schizophrenia in the prediction of treatment outcomes. We will replicate these results in additional samples and present a summary of latest evidence in an updated meta-analysis.