Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

Abstract

Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3 UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT ؋ DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score ‫؍‬ 4.3; familywise error (FWE) p ‫؍‬ 0.03), and in healthy volunteers alone (Z-score ‫؍‬ 4.7; FWEp ‫؍‬ 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis ؋ COMT ؋ DAT nonadditive interaction in the right orbital gyrus (Z-score ‫؍‬ 4.3; FWEp ‫؍‬ 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score ‫؍‬ 4.3; FWE p ‫؍‬ 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

“…Of course, this interpretation needs to be substantiated with biochemical evidence of hyper-or hypoexpression of the TCF4 gene in SCZ patients. Nevertheless, the inverted-U pattern of results has been reported for other genes such as the val/met polymorphism of the COMT gene (Barnett et al, 2008;Prata et al, 2009). Within research on SCZ patients and their controls, a SNP in the Neuregulin 3 gene also showed the same pattern of results, with the risk allele linked to better performance on a CPT task in SCZ patients but worse performance in healthy controls (Morar et al, 2011).…”

Behavioral Phenotypes in Schizophrenic Animal Models With Multiple Combinations of Genetic and Environmental Factors

“…Epistasis genetic studies of schizophrenia have reported gene-gene interactions between candidate genes (30). The potential value of genetic models for exploring gene-gene as well as gene-environment and environment-environment interactions relating to schizophrenia should be seriously considered (31).…”

DATby perceived MC interaction on human prefrontal activity and connectivity during emotion processing

“…The 10-repeat allele has been associated with greater levels of DAT expression (Heinz et al, 2000;Fuke et al, 2001;Mill et al, 2002;VanNess et al, 2005), although data in the opposite direction have also been reported (van Dyck et al, 2005). This polymorphism has also been associated with prefrontal and hippocampal activity during performance of cognitive tasks (Bertolino et al, 2006;Bertolino et al, 2008;Prata et al, 2009a;Prata et al, 2009b), with anxiety traits (Hunnerkopf et al, 2007) and with quality of parenting (Lee et al, 2010). More in detail, the DAT 3 0 VNTR 10 allele predicts greater scores for negative parenting in mothers when their offspring with ADHD symptoms present high child deviance (Lee et al, 2010).…”