Gene expression imputation provides clinical and biological insights into treatment-resistant schizophrenia polygenic risk

Abstract Treatment-resistant schizophrenia (TRS) is a complex phenotype with important implications in the clinical course of a disease that is both underdiagnosed and poorly treated. The identification of predictors and biomarkers for the early detection and treatment of TRS is a critical step. Large genome-wide association studies (GWAS) have revealed the polygenic nature of TRS. Gene expression imputation allowed the translation of genetic variants into regulatory mechanisms that can be used to assess its association with clinical features of TRS in a cohort with a first episode of psychosis (FEP). We used S-PrediXcan to perform transcriptome imputation in the largest GWAS of TRS to find genetically regulated gene expression (GReX) associated with TRS using GTEx brain tissues. Then, for each tissue. we constructed a GReX risk score (GReX-PS) of the identified genes in a sample of genotyped FEP patients to test the association of the GReX-PS with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS.