COMT andDRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders

Henderson, A. S.; Korten, A. E.; Jorm, Anthony F; Jacomb, P. A.; Christensen, Helen; Rodgers, Bryan; Tan, Xiaoyan; Easteal, Simon

doi:10.1002/(sici)1096-8628(20000207)96:1<102::aid-ajmg20>3.0.co;2-3

Cited by 82 publications

(48 citation statements)

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“…et al, 2003), neuroticism (Eley et al, 2003) (but not in all studies; Henderson et al, 2000), and aggression (Rujescu et al, 2003). It has also been strongly associated with one anxiety disorder in particularFpanic disorder ( (Ohara et al, 1998;Samochowiec et al, 2004) and, according to a recent meta-analysis, not with obsessive-compulsive disorder (Azzam and Mathews, 2003).…”

Section: Discussionmentioning

confidence: 96%

“…Two recent meta-analyses (that included a substantially overlapping set of studies) found evidence of an association between 5-HTTLPR and neuroticism, although less so with other anxiety-related constructs (eg harm avoidance) (Schinka et al, 2004;Sen et al, 2004a). Other genes tested for an association with anxiety-related traits have included monoamine oxidase type A (Eley et al, 2003;Jorm et al, 2000), cytochrome P450 2D6 isoenzyme (Roberts et al, 2004), GABA-A receptor alpha-6 subunit (Sen et al, 2004b) and, in a number of studies, catechol-O-methyltransferase (COMT) (Eley et al, 2003;Enoch et al, 2003;Henderson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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COMT Polymorphisms and Anxiety-Related Personality Traits

Stein

Fallin

Schork

2005

Neuropsychopharmacol

198

128

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High neuroticism and low extraversion are characteristic of anxiety-prone individuals. A functional variant in the catechol-Omethyltransferase (COMT) gene, the Val158Met ('val/met') polymorphism, has been associated in some prior studies with several phenotypes, including neuroticism. We tested the hypothesis that the val158met polymorphism would be associated with both high neuroticism and low extraversion, making it a plausible candidate locus for anxiety susceptibility. To determine whether val158met is responsible for these effects, we also evaluated the association with haplotypes that included two other SNPs within the COMT gene. We collected a sample of 497 undergraduate college students who were phenotyped on a personality inventory (the NEO-Personality Inventory-Raised (NEO-PI-R)). Subjects were genotyped for three COMT polymorphisms: the well-studied nonsynonymous SNP rs4680 that generates a valine-to-methionine substitution (val158met), rs737865 (near exon #1), and rs165599 (also functional, near the 3 0 -UTR). Together, these three SNPs define a haplotype that is associated with reduced COMT expression in human brain. Logistic regression analyses were used to examine the effects of individual SNPs on extraversion and neuroticism scores. Score tests for association between these traits (quantitatively and dichotomously considered) and haplotypes were also conducted. We evaluated potential for population stratification artifact by genotyping a set of 36 unlinked highly polymorphic markers previously demonstrated to distinguish sufficiently ancestry of major American populations. Two of the SNPs (rs4680 ('val/met') and rs737865) were significantly associated with (low) extraversion and, less consistently, with (high) neuroticism, with effects confined to women. A significant association between COMT haplotype and (low) extraversion and (high) neuroticism was also observed. Formal testing showed that population structure did not explain the findings. These data suggest that involvement of the COMT locus in susceptibility to anxiety-related traits (ie low extraversion and high neuroticism) is unlikely to be wholly accounted for by the well-studied rs4680 ('val/met') polymorphism. Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

COMT Polymorphisms and Anxiety-Related Personality Traits

Stein

Fallin

Schork

2005

Neuropsychopharmacol

198

128

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“…However, this appears to be somewhat at odds with a number of prior studies of neuroticism and other anxiety-related traits and symptoms (see Table 1). While several of the smaller studies reported marginally significant associations with the met allele or met-met genotype, the two largest studies either found no association with this locus (62) or association with the opposite (val) allele (4). Among those studies, only Stein and colleagues examined the effects of markers other than rs4680 (7).…”

Section: Discussionmentioning

confidence: 99%

Catechol-O-Methyltransferase Contributes to Genetic Susceptibility Shared Among Anxiety Spectrum Phenotypes

Hettema

Bukszár

et al. 2008

Biological Psychiatry

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“…No evidence of association with alcoholism was found in a case-control study from Japan 10 and no association with personality traits conferring vulnerability to alcoholism was found in a community sample from Australia. 11 To further investigate the role of the COMT lowactivity allele in alcoholism and extend the analysis to alcoholism with early onset, we tested the transmission of low-vs high-activity alleles from parents to alcoholic offspring. The use of a family-based association approach avoids the problem of case-control association studies in which false positive results can be produced as a result of hidden population stratifications.…”

Section: Catechol-o-methyltransferasementioning

confidence: 96%

Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach

et al. 2000

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Catechol-O-methyltransferase (COMT) is a major component of the metabolic pathways of neurotransmitters such as dopamine, adrenaline, and noradrenaline. The activity of COMT is known to vary within the population; it exists in common high-and low-activity forms that are determined by a Val → Met polymorphism at amino acid position 108/158 (in soluble or membranebound COMT). Recently, the low-activity allele was reported to contribute to the development of late-onset alcoholism in men. 1 The present study extends this study by utilizing a family-based association approach, and by including individuals with early-onset alcoholism. Although no significant transmission disequilibrium was found in the overall sample of 70 parent/offspring trios (TDT = 1.43, P = 0.23), we observed a preferential transmission of the low-activity allele to patients with an early onset of disease (n = 32, TDT = 4.83, P = 0.028). Our results provide further evidence for an involvement of the COMT low-activity allele in the development of alcoholism and demonstrate the need for further studies in large samples of alcoholic patients. Molecular Psychiatry (2001) 6, 109-111. Catechol-O-methyltransferase(COMT) is a biotransformation enzyme that inactivates biologically active or toxic catecholamines. It is a major component of the metabolic pathways of neurotransmitters such as noradrenaline, adrenaline and dopamine. 2 A single gene encodes membrane-bound (MB-COMT) and soluble (S-COMT) forms of the enzyme, which differ by a 50-amino acid hydrophobic N-terminal sequence that is present in the MB form. 3 A common genetic polymorphism in humans is associated with a three-to-fourfold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. [4][5][6] It was shown that this polymorphism is due to a G → A transition at codon 108 (158) of S-COMT (MB-COMT), that leads to a valine → methionine substitution. The valine → methionine substitution results in a low-activity allele. 6,7 In a global survey of populations, it was shown that frequencies of COMT high-and low-activity alleles vary greatly among ethnic groups. 8 Tiihonen and colleagues recently, 1 in this journal, reported a positive association between the COMT lowactivity allele and development of alcoholism. By applying a case-control design, they studied genotype and allele frequencies in a sample of 123 Finnish male alcoholics with late onset (over 25 years) and two independent sets of controls (3140 Finnish blood donors and 267 race-and gender-matched controls). The lowactivity allele was found to increase the risk for alcoholism, with an odds ratio of 2.51 (P = 0.006) for individuals homozygous for the low-activity allele vs those homozygous for the high-activity allele. Further support for a role of the COMT low-activity allele in drinking behavior was obtained in a population sample of 896 middle-aged Finnish men: men homozygous for the low-activity allele reported 27% higher weekly alcohol consumption compared with men from the two ot...

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COMT andDRD3 polymorphisms, environmental exposures, and personality traits related to common mental disorders

Cited by 82 publications

References 50 publications

COMT Polymorphisms and Anxiety-Related Personality Traits

COMT Polymorphisms and Anxiety-Related Personality Traits

Catechol-O-Methyltransferase Contributes to Genetic Susceptibility Shared Among Anxiety Spectrum Phenotypes

Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach

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