Polygenic risk scores for schizophrenia and treatment resistance: New data, systematic review and meta-analysis

Abstract

Although treatment-resistant schizophrenia (TRS) is an important and frequent problem with a specific treatment, clozapine, its biological determinants are poorly understood. At the genetic level, most studies of association between schizophrenia polygenic risk score (SCZ PRS) and TRS did not reach statistical significance. However, no systematic review or meta-analysis of this type of study has been conducted. In this work, we first performed an association study between SCZ PRS and TRS in a sample of 427 patients with schizophrenia. Then, we carried out a systematic review and meta-analysis of all available data. PubMed was searched for articles reporting association between SCZ PRS and TRS, defined as use of clozapine or failure of two sequentially prescribed antipsychotics. The association in our sample was not statistically significant. Five studies met the inclusion criteria, involving 7309 patients, 2386 (33 %) with TRS. Fixed effect model meta-analysis revealed a statistically significant association with TRS status (OR = 1.090, 95 % CI = 1.030–1.154; P = 0.0027; I2 = 0.00 %). The robustness of the result was demonstrated by maintaining a statistically significant association in all sensitivity analyses, such as a leave-one-out approach or use of a random effects model. Therefore, at least part of the genetic susceptibility to TRS is shared with that of schizophrenia. However, our results did not support the clinical utility of the SCZ PRS in its current stage due to the small effect size. Improvements in PRS estimation and combination with other predictors may lead to future use in stratification of patients.