LAUSR

Background Schizophrenia (SCZ) is a severe mental disorder affecting ~1% of the population and is characterized by the presence of psychosis and other features, such as negative (i.e., flattened affect and social withdrawal) and disorganization symptoms (e. g. impaired cognitive function, disorganized speech and behavior). Symptomatic and psychosocial deterioration progress rapidly during the period just after the onset of the disorder, termed the First Episode of Schizophrenia (FES). In this study, we aimed to test if the SCZ Polygenic Risk Score (PRS) was associated with clinical symptoms at the FES, nine weeks after initiation of risperidone treatment (FES-9W) and with the response to risperidone. Methods We performed a detailed clinical assessment of 60 antipsychotic naive patients in their FES and, again, after nine weeks of standardized treatment with Risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson Regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered as significant a p-value Results The polygenic risk score was significantly different between cases and controls with a best p-threshold of 0.0112 (NSNPs=21,622) and an explained variance of 0.19 (Naegelkerk's pseudo-r2). Within-cases, we found a positive association of the best PRS score with the PANSS excitement factor (five-factor model) (p-value=0.0003). The PRS was slightly positively correlated with depressive symptoms at baseline (CDSS total, p-value=0.003) but was negatively associated with depressive symptoms after risperidone treatment (CDSS total, p-value=0.001). Looking at response to risperidone, we observed a positive association for ΔCDSS (p-value=0.0006). However, there was no correlation between Δtotal PANSS and PRS. Discussion We verified that the schizophrenia PRS was also able to distinguish cases from control in this south-eastern Brazilian sample, with a similar variance explained (~0.19, observed scale) to that seen in Northern European populations. One strength of our study is that all patients were antipsychotic-naive at the baseline and received the same antipsycotic treatment for relatively the same time. It is well known that some patients may have an increase of depressive symptoms once the positive symptoms remit, however, there is no study so far that evaluated the relation between PRS and post-schizophrenia depression. Taken together, these results suggest that FES patients who present with higher depressive and excitement symptoms and who show reduction in these dimensions after treatment with risperidone have a significantly higher genetic risk for SCZ (as measured by PRS). These results highlight the importance of studying schizophrenia, and other disorders, in the early stages to understand the relationship between polygenic genetic risk and phenotypic features.