Genetic variants in COMT and neurocognitive impairment in families of patients with schizophrenia

Abstract

This study examined the relations of genetic variants in catechol-O-methyltransferase (COMT) gene, including rs737865 in intron 1, rs4680 in exon 4 (Val158Met) and downstream rs165599, to schizophrenia and its related neurocognitive functions in families of patients with schizophrenia. Totally, 680 individuals from 166 simplex (166 affected members and 354 nonpsychotic firstdegree relatives) and 46 multiplex families (85 affected members and 75 nonpsychotic first-degree relatives) were interviewed using Diagnostic Interview for Genetic Studies, administered Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT), and drawn for venous blood. Both categorical (dichotomizing families on affected members' neurocognitive performance) and quantitative approaches toward the WCST and CPT performance scores were employed using the family-based association test and the variance components framework, respectively. Both false discovery rate and permutations were used to adjust for multiple testing. The genotypes of rs4680 were associated with both the WCST and CPT performance scores in these families, but not with schizophrenia per se in either whole sample or subgroup analyses. Meanwhile, the other two single nucleotide polymorphisms were differentially associated with the two tasks. For WCST indexes, regardless of subgroup analyses or quantitative approach, only rs737865 exhibited moderate associations. For CPT indexes, rs737865 exhibited association for the subgroup with deficit on CPT reaction time, whereas rs165599 exhibited association for the subgroup with deficit on CPT d0 as well as quantitative undegraded d 0 . Our results indicate that the genetic variants in COMT might be involved in modulation of neurocognitive functions and hence conferring increased risk to schizophrenia.

Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort

“…Hence the results should be interpreted with caution. In the same vein, a marginal association with rs4680, an exonic SNP at COMT was noted in our case-control sample and has also been reported by several other investigators (Handoko et al., 2005;Nunokawa et al, 2010;Liao et al, 2009; Okochi et al, 2009; Bhakta et al, 2012; Singh et al., 2012). Apart from these exonic variants, nominally significant SNP associations were also noted at all the other genes tested, except at SLC6A3 (Table I) in either case-control or family based analysis.…”

Influence of the COMT val108/158met polymorphism on continuous performance task indices

“…There is limited research investigating the influence of COMT val 108/158 met polymorphism on CPT performance and thus far, the findings have been mixed (Caldú et al, 2007; Eisenberg et al, 1999; Liao et al, 2009; MacDonald, Carter, Flory, Ferrell, & Manuck, 2007; Mills et al, 2004). Importantly, the exact nature of the role of COMT in cognitive function is unclear with regard to specificity.…”

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

“…73,251 Furthermore, this polymorphism has frequently been associated with WSCT performance, although recent studies and a meta-analysis have found that the association may only be small, although significant. 252,253 Finally, mutations in COMT have also been associated with social anhedonia. 254 In animal model studies, male homozygous Comt knockout mice showed a 2-to 3-fold increase in DA levels, although female mice did not.…”