Schizophrenia Polygenic Risk Score as a Predictor of Antipsychotic Efficacy in First-Episode Psychosis

Abstract

Objective: Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms; by contrast, polygenic risk scores (PRS) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. We examined whether PRS for schizophrenia are predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total n=510). Method: All subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard SNP arrays imputed to the 1000 Genomes reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by total symptom rating scales at baseline and week 12 or at the last follow-up visit before drop-out. Results: In the discovery cohort, higher PRS significantly predicted higher symptom scores at 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold of PT<0.01 gave the strongest result in the discovery cohort, and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater post-treatment symptoms in the combined replication analysis (p=.0095), and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18, p=0.002, 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than those with high PRS (OR=1.91 in Caucasian samples, p<0.01). Conclusion: Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.

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