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Schizophrenics' Responses to Antipsychotic Drugs Could be Predicted by Polygenic Risk Scores

NEW YORK (GenomeWeb) – An international team of researchers has found that the polygenic nature of schizophrenia may make polygenic risk scoring (PRS) a valuable predictor of the efficacy of antipsychotic drugs in schizophrenic patients suffering from a first episode of psychosis.

Pharmacogenomic studies of antipsychotics have typically examined the effects of individual polymorphisms. But genetic susceptibility to schizophrenia is highly polygenic, and there are many associated loci that can confer small effects by themselves, the researchers said. And although individual risk alleles may convey low odds for the condition, the combination of all such effects across the genome raises an individual's odds of developing it.

"Individuals scoring in the top decile are approximately 15 times more likely to manifest the illness compared with those in the bottom decile," the team wrote.

Given the power PRS has for explaining a person's susceptibility to the disease, the researchers asked whether such a scoring system could be used to predict treatment response. As they reported today in the American Journal of Psychiatry, the researchers examined 510 patients with first-episode psychosis split into four cohorts — 77 patients from the Zucker Hillside Hospital First-Episode schizophrenia trial comprised the discovery cohort, and the other patients were split into three replication cohorts.

The participants received initial treatment with antipsychotic medication and were all genotyped on standard single-nucleotide SNP arrays imputed to the 1000 Genomes Project reference panel. A PRS was computed for each patient based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium, and the patients' symptoms were measured at baseline and at week 12, or at the last follow-up visit before they dropped out of the study.

The researchers found that a higher PRS significantly predicted greater post-treatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was also significantly predictive of adjusted 12-week symptom scores, the researchers said. In contrast, they found that patients with low PRS were more likely to respond to treatment than patients with high PRS.

To explore the clinical significance of their findings, the researchers then calculated the response rate for each cohort, defining treatment response as a 50 percent reduction in total symptoms from baseline to the 12-week follow-up. They then divided each cohort into a high PRS group and a low PRS group and found that the response rate of low PRS group from all four cohorts was 60.9 percent compared to 52.1 percent in the combined high PRS group from all four cohorts.

Their observations led them to conclude that PRS burden may have potential utility as a prognostic biomarker. "In multiple cohorts of first-episode patients with nonaffective psychosis, we found that schizophrenia PRSs were significantly predictive of antipsychotic drug efficacy, with higher PRSs associated with poorer treatment response," the authors wrote. "These results suggest that polygenic burden may affect severity of illness, in addition to reflecting risk for developing psychosis. To the best of our knowledge, this is the first study to identify replicable effects of PRS in predicting antipsychotic efficacy in patients undergoing initial treatment for a first episode of illness."

The researchers noted that there are some limitations to their study. However, they are hoping to expand the study in order to develop clinical guidelines for the use of polygenic risk scores and other predictors, such as brain scans, in the treatment of schizophrenia.