COMT Val158Met-Stress Interaction in Psychosis: Role of Background Psychosis Risk

Background: The interplay between the catechol-O-methyltransferase (COMT) Val158Metpolymorphism and environmental stress may have etiological relevance for psychosis, butdifferential effects have been reported in healthy control and patient groups, suggesting thatCOMT Val158Met interactions with stress may be conditional on background genetic riskfor psychotic disorder. Methods: Patients with a nonaffective psychotic disorder (n=86)and control participants (n=109) were studied with the experience sampling method (astructured diary technique) in order to assess stress, negative affect and momentary psy-chotic symptoms in the flow of daily life. Results: Multilevel analyses revealed significantthree-way interactions between group status (patient or control), COMT genotype and stressin the model of negative affect (χ2(2)=13.26,P<0.01) as well as in the model of momen-tary psychotic symptoms (χ2(2)=6.92,P<0.05). Exploration of the three-way interactionrevealed that in patients, COMT genotype moderated the association between stress andnegative affect (χ2(4)=11.50,P<0.005), as well as the association between stress and mo-mentary psychosis (χ2(4)=12.79,P<0.005). Met/Met genotype patients showed signifi-cantly increased psychotic and affective reactivity to stress in comparison to the Val/Met andVal/Val genotypes. In contrast, healthy controls did not display large or significant COMTVal158Met X stress interactions. Conclusions: Important differences exist in the effect ofCOMT Val158Met on stress reactivity, which may depend on background risk for psychoticdisorder. Differential sensitivity to environmental stress occasioned by COMT Val158Metmay be contingent on higher order interactions with genetic variation underlying psychoticdisorder.