To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O
-methyl transferase (COMT
Met and dopamine receptor 3 (DRD3
Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT
genotype combinations on cognitive performance.
For executive functioning, COMT
Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT
Met allele frequency increased, executive functioning worsened. COMT
Met/Met patients carrying the DRD3
Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3
combination significantly differed from all DRD3
Gly/Gly combinations (p < 0.05), from COMT
Ser/Gly (p = 0.02), and from COMT
Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001).
Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.
Keywords: Endophenotype; psychosis; genetics; dopamine; executive function