Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5? nuclease assay

Zhu, Guoqiang; Lipsky, Robert H.; Ali, Sameer; Hyde, Thomas M.; Kleinman, Joel E.; Akhtar, Longina; Mash, Deborah C.; Goldman, David

doi:10.1007/s00213-004-1938-z

Cited by 57 publications

(47 citation statements)

References 29 publications

(37 reference statements)

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“…The Val158 allele is approximately three times more thermostable than Met158 at normal body temperature, and has 40% higher activity 72 . Furthermore, Val158 and Met158 are found on differentially expressed haplotype backgrounds 73 of ancient origin, as indicated by their opposite (yin-yang) allelic configurations (a 5-locus haplotype pattern of 1122Val versus 2211Met) that are both abundant in populations worldwide 74 . The haplotype analyses predict variation in COMT expression, and it is likely that COMT linkage studies will incorporate haplotype information to capture more details on the functional genetic variation of this gene.…”

Section: Genes and Neurobiologiesmentioning

confidence: 99%

The genetics of addictions: uncovering the genes

2005

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Section: Genes and Neurobiologiesmentioning

confidence: 99%

The genetics of addictions: uncovering the genes

2005

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“…Recently, the low activity Met allele has been reported as a risk factor for cognitive decline in 22q11DS. 43 Most work to date has focussed on the Val/Met polymorphism and other variants reported to be associated with altered mRNA expression 44,45 have not been widely studied. However, on the current evidence, the mechanism for the cognitive effects at COMT is unlikely to be simple.…”

Section: Association Studies Of Comt and Frontal Lobe Functionmentioning

confidence: 99%

“…This suggestion is broadly compatible with the demonstration of cis-acting loci that modify the expression of COMT mRNA independent of the Val/ Met locus. 44,45 However, there are also data that argue strongly against the existence of more than one even moderately common functionally relevant polymorphism in COMT. Thus, while Chen et al 10 demonstrated that brain COMT enzyme activity is associated with the Val/Met locus, this did not correlate with the markers that we and others have associated with mRNA expression 44,45 or with schizophrenia.…”

Section: Schizophreniamentioning

confidence: 99%

The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons

2006

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The enzyme catechol-O-methyl transferase (COMT), identified in the 1950s, is involved in catabolism of monoamines that are influenced by psychotropic medications, including neuroleptics and antidepressants. The COMT gene lies in a chromosomal region of interest for psychosis and bipolar spectrum disorder and a common polymorphism within the gene alters the activity of the enzyme. As a consequence, COMT has been one of the most studied genes for psychosis. On the basis of prior probabilities it would seem surprising if functional variation at COMT did not have some influence either on susceptibility to psychiatric phenotypes, modification of the course of illness or moderation of response to treatment. There is now robust evidence that variation at COMT influences frontal lobe function. However, despite considerable research effort, it has not proved straightforward to demonstrate and characterise a clear relationship between genetic variation at COMT and psychiatric phenotypes. It is of course, possible that COMT will turn out to be an unusually intractable case but it seems more likely that the experiences with this gene will provide a foretaste of the complexity of genotype-phenotype relationships that will be found for psychiatric traits. In this review, we consider the current state of evidence and the implications both for further studies of COMT and more generally for studies of other genes.

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“…The valine allele (472G) has initially been reported to result in a three-to fourfold higher COMT activity as compared to the methionine allele (472A) (Lachman et al, 1996). However, the valine allele appears to be less expressed in the brain as compared to the methionine allele (Bray et al, 2003;Zhu et al, 2004), which slightly mitigates the effect to about 40% increased enzyme activity as conferred by the valine allele (Chen et al, 2004). The COMT val158met polymorphism has repeatedly been investigated for association with major depression with contradictory reports of no association (Kunugi et al, 1997;Frisch et al, 1999;Cusin et al, 2002;Serretti et al, 2003), possible association with the valine allele (Massat et al, 2005;Funke et al, 2005) or conversely the methionine allele (Ohara et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression

Baune

Hohoff

Berger³

et al. 2007

Neuropsychopharmacol

133

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In several previous biochemical, pharmacological, and genetic studies, the catechol-O-methyltransferase (COMT) has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of affective disorders. In the present study, 256 patients with major depression (DSM-IV) of Caucasian descent were genotyped for the functional COMT val158met polymorphism and characterized for clinical response to antidepressive pharmacological treatment as measured by intra-individual changes of Hamilton Depression (HAM-D-21) scores over 6 weeks. The COMT 158val/val genotype conferred a significant risk of worse response after 4-6 weeks of antidepressant treatment in patients with major depression (week 4: p ¼ 0.003; week 5: po0.0001; week 6: po0.0001) after Bonferroni correction for multiple comparisons. The present results strongly point toward a negative influence of the higher activity COMT 158val/ val genotype on antidepressant treatment response during the first 6 weeks of pharmacological treatment in major depression, possibly conferred by consecutively decreased dopamine availability. This finding suggests a potentially beneficial effect of an antidepressive addon therapy with substances increasing dopamine availability individually tailored according to COMT val158met genotype.

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Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5? nuclease assay

Abstract: COMT alleles are differentially expressed. The Met158 allele predicts higher mRNA expression in both brain and lymphoblasts. As exemplified here, the RT-coupled 5' nuclease assay is a reliable method for the quantitative evaluation of cis-acting regulatory effects.

Cited by 57 publications

References 29 publications

The genetics of addictions: uncovering the genes

The genetics of addictions: uncovering the genes

The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons

Association of the COMT val158met Variant with Antidepressant Treatment Response in Major Depression

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