American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
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Am. J. Med. Genet. B Neuropsychiatr. Genet. · Apr 2009
Association between catechol O-methyltransferase (COMT) haplotypes and severity of hyperactivity symptoms in adults.
It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930-1933]. ⋯ Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.
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Am. J. Med. Genet. B Neuropsychiatr. Genet. · Sep 2008
DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first-episode psychosis adolescents.
Catechol-O-methyltransferase (COMT) and dopamine receptors 2 (DRD2) and 3 (DRD3) have been associated with a higher risk of developing psychosis and with dopaminergic system (DAS) regulation. Frontal cognitive functioning has been proven to be a useful endophenotype for psychosis and it is partially controlled by the DAS. Val158Met (rs4680, COMT), Taq IA (rs1800497, DRD2) and Ser9Gly (rs6280; DRD3) polymorphisms were analyzed in a sample of 84 adolescent Caucasian patients with first-episode psychosis (ages 11-17) and 85 healthy Caucasian controls (ages 10-17). ⋯ The DRD3 Ser9Gly polymorphism seems to be involved with prefrontal cognition. This effect seems to be heterogeneous in terms of cognitive paradigms. The lack of association between COMT and DRD2 genotypes and cognition in our sample may be partially explained by the young age of the sample and the clinical heterogeneity of the patients.
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Am. J. Med. Genet. B Neuropsychiatr. Genet. · Sep 2008
Putative role of the COMT gene polymorphism (Val158Met) on verbal working memory functioning in a healthy population.
Working memory has been described as a neurocognitive probe of prefrontal brain functioning. Genetic variability related with catechol-O-methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of working memory tasks in both schizophrenic patients and healthy subjects, although inconsistencies across studies have been found. This may be related to the existence of different working memory components, processes and modalities, which may have different sensitivities to subtle changes in dopamine levels and, therefore, the effect of the underlying COMT Val158Met genetic variability. ⋯ Moreover, the analysis for linear trend found that Met allele carriers showed significantly better performance than Val/Val individuals (B = 0.58 P = 0.031), although evidence for a linear trend was not found. None of the WCST indices differed among genotypes. Consistent with the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine-dependent prefrontally related neurocognitive functions, the Letter-Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non-clinical sample.
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Am. J. Med. Genet. B Neuropsychiatr. Genet. · Sep 2008
Polymorphisms in the catechol-O-methyltransferase (COMT) gene influence plasma total homocysteine levels.
Elevated plasma total homocysteine (tHcy) is a risk factor for various disorders. We investigated whether functional polymorphisms in catechol-O-methyltransferase (COMT) influence tHcy, since COMT activity produces S-adenosylhomocysteine (SAH), a homocysteine precursor. We hypothesized that high activity COMT variants would be associated with high tHcy, since they presumably result in increased formation of SAH. ⋯ High activity variants of COMT interact with the low activity variant of MTHFR to increase tHcy levels. The effect on tHcy may contribute to the reported associations of COMT genotype with psychiatric and neurobiological phenotypes. The results also indicate that COMT activity may influence a broader range of biochemical pathways than hitherto appreciated.
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Am. J. Med. Genet. B Neuropsychiatr. Genet. · Sep 2007
Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction.
Variants of the opioid receptors are the obvious candidates underlying addiction. The kappa opioid receptor (KOR) system seems to play a role in stress responsivity, opiate withdrawal and responses to psycho-stimulants, inhibiting mesolimbic dopamine. KOR gene polymorphisms have been reported to contribute to predisposition to voluntary alcohol-drinking behavior in experimental animals. ⋯ The frequency of KOR 36G > T SNP was significantly higher among heroin-dependent individuals compared with control subjects (Fisher's exact = 0.044; Pearson chi(2) = 4.2734, P = 0.039; likelihood ratio chi(2) tests = 4.6156, P = 0.032). Although KOR silent polymorphisms may apparently have no consequences on mRNA transcription, post-transcriptional mechanisms, such as mRNA stability, translation efficiency, and regulability may impair the function of kappa receptors system, with increased risk for substance use disorders. In specific, the neurobiological changes induced by mu-kappa opioid imbalance could underlie vulnerable personality traits and risk behavior.