Genetic evidence for causal relationship between general cognition and treatment resistance in schizophrenia

Treatment-resistant schizophrenia (TRS) is characterized by symptoms unresponsive to standard antipsychotics, possibly representing a distinct subtype of schizophrenia with unique neurobiological mechanisms. TRS may share neurodevelopmental mechanisms with cognitive impairment, which is also frequently resistant to treatment. However, the association between TRS and cognitive impairment remains inconclusive in the literature. This study aims to investigate the genetic associations between TRS and general cognitive function, operationalized by general intelligence (GF) and educational attainment (years of education [EAY] and college completion [CC]), by analyzing genome-wide association study (GWAS) summary statistics using Two-sample Mendelian Randomization (MR) methodology. We also employed conditional false discovery rate (cFDR) analyses to increase statistical power to identify genetic associations for TRS, leveraging on association results for GF and EAY. Negative genetic association between general cognition and treatment resistance in schizophrenia was revealed by MR results. Four previously unreported TRS risk loci conditioning on general cognition at cFDR <0.01 were identified. The shared credible genes mapped to loci was TMX1. The gene sets enriched with identified shared genes, including GOCC_INFLAMMASOME_COMPLEX, GOCC_NLRP3_INFLAMMASOME_COMPLEX, and GOMF_CASPASE_BINDING gene sets, were related to inflammatory processes. These results provide evidence on the possible causative link between general cognition or a closely correlated trait and TRS, and the presence of complex and unique biological mechanisms in the development of treatment-resistant schizophrenia.