FOXP2 AND SCHIZOPHRENIA

Abstract

candidate gene for schizophrenia. Previous studies indicated a possible trade-off effect of COMT with increased COMT activity (Val/Val genotype) resulting in compromised cognition but increased resilience to stress, and decreased COMT activity (Met/Met genotype) resulting in improved cognition but greater reactivity to stress. Part of the phenotypic variability associated with COMT Val158Met has been proposed to be caused by variations in genes that collaborate with COMT, or modify COMT function. A strong candidate gene is the gene encoding for methylenetetrahydrofolate reductase (MTHFR). MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in the one-carbon metabolism, which has an important role in DNA methylation. The two common functional polymorphisms, C677T and A1298C, both result in reduced MTHFR enzyme activity. We hypothesized that interaction between MTHFR and COMT Val158Met would predict psychotic reactivity to stress in patients with non-affective psychotic disorder. Methods: A sample of 98 patients with non-affective psychotic disorder and 118 controls were genotyped for MTHFR C677T, MTHFR A1298C, and COMTVal158Met (rs4680, rs1801131, and rs1801133). Psychotic reactivity to daily life stressors was measured with the experience sampling method. Results: MTHFRC677Tgenotypemoderated the interaction between COMT Val158Met genotype and stress in patients (p<0.0001), but not in controls (p=0.68). Carriers of MTHFR 677 T-allele and COMT Met/Met displayed the largest psychotic reactivity to daily life stressors. Discussion: The results indicate for the first time that MTHFR moderates the effect of COMT genotype on psychotic reactivity to daily life stress, and that this may selectively occur in patients. These findings are in line with an earlier finding on moderation of MTHFR on COMT effects on cognition in schizophrenia patients and increase our understanding of the molecular mechanisms underlying COMT's trade-off effects. Although replication of our findings is warranted, the data suggest that MTHFR-dependent molecular processes, such as the one carbon metabolism and DNA methylation, affect functioning of COMT in schizophrenia.