<p>Schizophrenia is a heterogeneous disorder, with subpopulations showing a relatively higher heritable predisposition based on many common genetic variants with minimal effects, whereas other subpopulations likely have alternative pathogenic backgrounds, including rare genetic variants with large effects. These heterogeneities may hinder the identification of molecular profiles related to the disorder’s pathogenesis. Therefore, this study aimed to identify transcriptional profiles specific to patients with schizophrenia with high heritable predisposition, indicated by high polygenic risk scores (PRS), and an alternative subgroup with low PRS. RNA-seq-based transcriptome data of the prefrontal cortices were compared among subgroups of patients with high PRS (PRS at or above the median; <i>n</i> = 12), low PRS (PRS below the median; <i>n</i> = 11), and controls (<i>n</i> = 21). Gene-category enrichment analysis of 584 differentially expressed genes (DEGs) identified 8 DEGs associated with DNA repair. Additionally, the expression levels of these DNA repair-related genes were associated with the general psychopathology scale, raising the hypothesis that oxidative stress accumulation, indicated by superoxide dismutase 2 expression may contribute to DNA repair activation. Furthermore, the expression levels of six DNA repair-related genes were significantly linked to the severity of the general psychopathology scale, suggesting that DNA repair might affect the clinical phenotypes of schizophrenia. This study used PRS to stratify patients with schizophrenia, highlighting the potential role of DNA repair-related pathways to the heterogeneity of schizophrenia. Understanding the role of DNA repair could lead to personalized treatments that target oxidative stress-related molecules.</p>