Genetic risk for neurodevelopmental disorders as a potential factor affecting antipsychotic responsiveness in schizophrenia: a postmortem brain study

Introduction Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder. Its genomic architecture reportedly overlaps with that of neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the effect of genomic risk for ADHD and ASD on SCZ symptoms remains unclear. Method We obtained genome-wide association study (GWAS) data from the postmortem brains of 24 patients with SCZ and 48 controls and calculated the polygenic risk scores (PRSs) for ADHD (ADHD-PRS) and ASD (ASD-PRS) using publicly available GWAS data. For 19 patients with SCZ whose antemortem clinical information was available, we conducted correlation analyses between PRSs, severity of SCZ symptoms, and the antipsychotic responsiveness score (ARS). Additionally, we divided the patients into two subgroups based on ADHD-PRS (high and low ADHD-PRS groups) and performed exploratory gene expression analyses and subsequent pathway analysis in the prefrontal cortex. Results The ARS of positive symptoms (ARS-PS) demonstrated a suggestive negative correlation with ADHD-PRS and a positive correlation with ASD-PRS although these associations did not survive multiple testing correction. No correlation was observed between the ARS of general psychopathology or the ARS of negative symptoms and either ADHD-PRS or ASD-PRS. Gene expression analysis identified 1,773 DEGs, including neuropsychiatric disorder-related genes including CHRNB2 . These DEGs were enriched in pathways associated with the neuronal system and mitochondrial function. Discussion Our findings suggest that the genomic risk for neurodevelopmental disorders may affect the antipsychotic responsiveness of patients with schizophrenia and implicate translational alterations in potential marker molecules in this phenotype. Due to the limited sample size in the current study, further investigation on the large cohort is required to verify our exploratory findings.