Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

Abstract

The catechol-O-methyltransferase (COMT) Val 158 Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n = 1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d = 0.29; 95% confidence interval (CI) 0.02-0.55; P = 0.03), but this was not supported in the patient sample (d = À0.07; 95% CI À0.40 to 0.26; P = 0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val 158 Met genotype and executive function in healthy individuals but not in schizophrenia.

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…Not all COMT genotypic associations are demonstrably sexually dimorphic; eg on any risk for schizophrenia that it confers (Glatt et al, 2003;Fan et al, 2005), or its influence on Wisconsin Card Sort Test performance (Barnett et al, 2007b) and on homocysteine metabolism (Tunbridge et al, 2007c). Neither is COMT the only autosomal gene for which sexually dimorphic genetic associations with psychiatric phenotypes have been reported; eg HTR2A with OCD in women (Enoch et al, 2001), MTHFR with schizophrenia in men (Sazci et al, 2005;Kempisty et al, 2006), and ACVII with depression in women (Hines et al, 2006).…”

“…In consequence, dopamine signaling is likely to be enhanced in Met 158 -compared to Val 158 -carrying individuals, consistent with pharmacological evidence (Tunbridge et al, 2004a). Following the landmark study of Egan et al (2001), a range of studies have shown that the Val 158 Met allele has a small but significant impact on prefrontal cognitive performance and efficiency, with Met 158 -carrying individuals performing better and/or more efficiently than Val 158 -carrying individuals (Barnett et al, 2007b). Conversely, the Val 158 allele is associated with more 'flexible' cognitive responses (Bilder et al, 2004), especially during emotional processing (Smolka et al, 2005;Drabant et al, 2006).…”

“…Many parameters of brain function and structure vary between men and women (eg Gur et al, 1995;Murphy et al, 1996;De Courten-Myers, 1999;De Bellis et al, 2001;Goldstein et al, 2001;Preece and Cairns, 2003;De Vries, 2004), and most psychiatric disorders show sex differences in one or more variables including incidence, age at onset, clinical features, and outcome (eg Lensi et al, 1996;Tamminga, 1997;Piccinelli and Wilkinson, 2000;Aleman et al, 2003;Baron-Cohen et al, 2005). These dimorphisms are usually ascribed primarily to the influence of sex hormones (Collaer and Hines, 1995;Rubinow and Schmidt, 1996;Seeman, 1997;Kelly et al, 1999), as well as to the actions of sex chromosome genes (Vawter et al, 2004;Cutter et al, 2006;Davies and Wilkinson, 2006).…”

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

“…The Val158Met (rs4680) polymorphism is the most common variation in the COMT gene (Tunbridge et al., 2006) whereby a single guanine to arginine (G/A) base pair substitution at codon 158 results in a valine (Val) to methionine (Met) substitution, which leads to ~40% lower enzyme activity in the Met carriers (Chen et al., 2004). Research investigating the association between genetic variation in COMT Val158Met and executive function, attention, and working memory in healthy people as well as schizophrenic patients has had mixed findings (Barnett, Jones, Robbins, & Müller, 2007; Barnett, Scoriels, & Munafò, 2008). It is possible that the presence of adverse life events may mediate some of the effects of this COMT variant on cognition.…”

Modulating effect of COMT genotype on the brain regions underlying proactive control process during inhibition

“…The impact of COMT genotype was frequently reported on behavioral performance when multi-compound executive tasks were administered, such as the Wisconsin Card Sorting Test or planning and decision making tasks. Most of these studies reported a better performance in the Met allele carriers population (Barnett, et al, 2007;Bruder, et al, 2005;Caldu, et al, 2007;Egan, et al, 2001;Malhotra, et al, 2002;Minzenberg, et al, 2006;Rosa, et al, 2004;Roussos, et al, 2007). However, when tasks assessing more specific executive processes were used, the advantage related to the Met polymorphism was not so obvious.…”