Evidence that the COMT^Val158Met polymorphism moderates sensitivity to stress in psychosis: An experience‐sampling study

Abstract

Gene-environment interactions involving the catechol-O-methyltransferase Val(158)Met polymorphism (COMT(Val158Met)) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty-one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMT(Val158Met) genotype and ESM stress in the model of NA was found for patients (interaction chi(2) = 7.4, P = 0.02), but not for controls (interaction chi(2) = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMT(Val158Met) genotype and ESM stress was also apparent (interaction chi(2) = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMT(Val158Met) polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene-environment interaction mechanisms in the formation of psychotic symptoms.

Stress-Related Methylation of the Catechol-O-Methyltransferase Val158Allele Predicts Human Prefrontal Cognition and Activity

“…Consistently, the Val allele has been repeatedly associated with inefficient prefrontal activity, that is, greater activity for a given level of behavioral performance (Egan et al, 2001;Bertolino et al, 2004;Mier et al, 2010). Other studies have also indicated that the Val 158 allele is a protective factor against stress, suggesting specific behavioral correlates of pleiotropic effects (Mattay et al, 2003;Papaleo et al, 2008;van Winkel et al, 2008;Walder et al, 2010). Consistent with this earlier body of work, here we have demonstrated that methylation of the Val allele in homozygous subjects is sensitive to stress; is correlated with WM behavioral performance; and interacts with stress, modulating PFC responses during WM performance such that greater stress and lower methylation are correlated with more inefficient prefrontal activity.…”

“…Catechol-O-methyltransferase (COMT), a key enzyme for inactivation of prefrontal DA (Gogos et al, 1998), contains a SNP (rs4680, G3 A, Val3 Met), in which the ancestral Val allele is associated with greater enzyme activity, blunted stress responses, and greater prefrontal activity during WM, that is, reduced efficiency (Egan et al, 2001;Chen et al, 2004;Papaleo et al, 2008;van Winkel et al, 2008;Mier et al, 2010;Walder et al, 2010). Notably, rs4680 in COMT exon 4 also abolishes a CpG site so that each Val allele has one CpG site and the Met allele has none.…”

Stress, Schizophrenia and Bipolar Disorder

“…Study of the additive interaction of genes and trauma demonstrate worse cognitive functioning in first-episode patients with a history of physical childhood trauma (neglect or abuse) carrying the short-version of the serotonin transporter (5-HTTLPR) gene (Aas et al 2012); in addition, four studies have shown increased symptoms in psychotic individuals homozygous for the Met allele of the COMT Val 158 Met genotype in response to daily stress or in those with a history of childhood trauma (van Winkel et al 2008a;Collip et al 2011;Peerbooms et al 2012;Green et al 2014). These and other emerging studies of epigenetic processes highlight the likely interaction of genetic variations with traumatic experiences that may be also affected by epigenetic processes.…”

Psychiatry beyond labels: introducingcontextual precision diagnosisacross stages of psychopathology

“…in terms of heritability and familial resemblance (Jacobs et al 2006;Menne-Lothmann et al 2012), but particularly in terms of the genetics underlying environmental sensitivity (Myin-Germeys et al 2001;van Winkel et al 2008;Wichers et al 2008a,b;Lataster et al 2009;Simons et al 2009;Collip et al 2011;Peerbooms et al 2012), a mechanism referred to as geneenvironment interaction.…”