COMT rs4680 and DAOA rs947267 Polymorphism Interact to Influence Cognition and Psychiatric Symptoms in Chronic Schizophrenia

Dopaminergic and glutamatergic dysfunction, involving genes such as COMT and DAOA, is implicated in schizophrenia. However, large‐scale studies examining their interactions on cognitive and symptomatic outcomes remain scarce. COMT rs4680 and DAOA rs947267 polymorphisms were measured in chronic schizophrenics ( n = 758) and controls ( n = 416), and cognition and psychiatric symptoms were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Positive and Negative Syndrome Scale (PANSS). Both the dominant (OR = 0.582, p = 0.024) and heterozygous (OR = 0.533, p = 0.012) models revealed notable variations in genotype distribution between cases and controls for the COMT polymorphism. Among females, the COMT polymorphism conferred a risk under the recessive model (OR = 1.571, p = 0.045) but a protective effect under heterozygous (OR = 0.378, p = 0.026) and codominant (OR = 0.515, p = 0.005) models. Additionally, we found that the COMT Val and DAOA A alleles interacted synergistically to worsen immediate memory in patients with schizophrenia. A significant COMT × DAOA interaction on language ( p = 0.019) was revealed in schizophrenia but not in controls. Val/Val + A schizophrenia carriers exhibit poorer language performance than Met + A carriers (AA/CA genotypes) ( p = 0.019). Furthermore, Met + CC schizophrenia carriers demonstrated significantly higher PANSS‐G ( p = 0.020) or total PANSS scores ( p = 0.008) than Met + A carriers. These findings, derived from large‐scale empirical data, offer a more profound understanding of the complex regulatory mechanism between the dopamine and glutamate systems regarding cognition and clinical symptoms in chronic schizophrenia. This understanding may lead to the development of more effective treatments targeting both systems.