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Genes, cognition and brain through a COMT lens.

ABSTRACT: Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O-methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. Val158Met, a common, functional variant in the coding sequence that increases or decreases the enzymatic activity of the gene has been shown to impact the efficiency of prefrontally-mediated cognition, specifically executive functioning, working memory, fluid intelligence and attentional control. We review the rapidly evolving literature exploring the association between COMT genotype and cognitive performance, and illustrate how this polymorphism has served a pivotal role in characterizing various interacting dimensions of complexity in the relationship between genes and cognition. We review how Val158Met has been used to help develop and validate behavioral and neurophysiological phenotypes, as a critical tool in dissecting overlapping neural functional systems and exploring interactions within and between genes, and in exploring how gene effects on cognition are modulated by environmental, demographic and developmental factors. Despite the impressive range of findings, the COMT story is also a bracing reminder of how much work remains to translate this knowledge into practical clinical applications.

SUBMITTER: Dickinson D

PROVIDER: S-EPMC2760675 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Genes, cognition and brain through a COMT lens.

Dickinson D D Elvevåg B B

Neuroscience 20090513 1

Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O-methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. Val158Met, a common, functional variant in the coding sequence that increases or decreases the enzymatic activity of the gene has been shown to impact the efficiency of prefrontally-mediated cognition, specifically executive functioning, working memory, fluid inte ...[more]

PMID: 19446012

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Project description:BACKGROUND: Cognitive dysfunction is prevalen among brain tumor patients treated with radiotherapy (RT) and chemotherapy (CT). However, little is known about genetic risk factors that may moderate their vulnerability for developing cognitive impairment. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in three genes, Catechol-O-Methyl-Transferase (COMT), Brain-Derived-Neurotrophic-Factor (BDNF), and dystrobrevin binding protein 1 (DTNBP1), and cognitive functions in brain tumor survivors. METHODS: One hundred and fifty brain tumor patients participated in the study: ninety had been treated with RT ± CT, fifty-seven had CT alone, and three had no therapy. All Patients completed a battery of neuropsychological tests of attention, executive functions and memory, and provided a blood sample. Genotyping of SNPs in the BDNF (n = 9), COMT (n = 17) and DTNBP1 (n = 7) genes was performed. RESULTS: Linear regressions with stepwise backward elimination of SNPs based on change in AIC criterion, adjusting for age, education, and treatment type indicated a significant (p< 0.05) association between the COMT SNP rs4680 (Val158Met) and cognitive function, with lower working memory scores in homozygotes (G/G) and higher executive function and delayed recall scores in heterozygotes (A/G). Five additional SNPs in the COMT gene were significantly associated with lower scores in attention and executive functions. There were significant associations among five SNPs in the BDNF gene and lower performance in executive function, learning and delayed recall. Four SNPs in the DTNBP1 gene were associated with attention and memory scores. CONCLUSION: The findings suggest that in brain tumor patients, cognitive outcome may be differentially affected by polymorphisms in genes previously associated with executive and memory functions in healthy individuals and other clinical populations. Further work is underway to quantify the variation in cognitive outcomes explained by these polymorphisms.

Dataset Information

Genes, cognition and brain through a COMT lens.

Publications

Genes, cognition and brain through a COMT lens.

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