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

Abstract

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...

Lack of Association of Alcohol Dependence and Habitual Smoking With Catechol‐O‐methyltransferase

“…Due to the ascertainment and recruitment strategy, it was possible to perform analyses considering only those with early onset alcohol dependence. Previous analyses (Wang et al, 2001) reported that although there was no overall association between the Val158Met polymorphism and alcoholism in a study of 70 trios, nor in other subsets of the data based on gender or age, the Met158 allele was preferentially associated with early onset alcoholism in a subset of 28 trios having a male proband. In the present, larger family study, we found no evidence of association of the Val158Met polymorphism with either alcoholism or early onset alcoholism (Table 1), although the latter discrepancy may be due to our inclusion of females.…”

“…The Met158 allele has been associated with late onset alcoholism in men Tiihonen et al, 1999). This same allele has been associated with early onset alcoholism in one study (Wang et al, 2001) but not in others Ishiguro et al, 1999). The Met158 allele has also been associated with elevated weekly alcohol consumption in male social drinkers .…”

“…In several previous studies, association analyses focused on only men Tiihonen et al, 2000) or women (Enoch et al, 2006), or stratified the sample based on age of onset Tiihonen et al, 2000;Wang et al, 2001) or other comorbid phenotypes such as cigarette smoking (Enoch et al, 2006). To reduce the potential increase in false-positive results due to population stratification, our study was designed to employ family-based tests of association.…”

“…Individuals without a completed SSAGA (n = 123) were classified as unknown. In a previous study, an association was found with early onset alcoholism, defined as onset of DSM-IV alcohol dependence prior to 25 years of age (Wang et al, 2001). To test the potential association of COMT with early onset alcohol dependence, we identified a large subset of our sample (n = 503; 67% of the DSM-IV alcohol-dependent sample) with early onset alcohol dependence (by the same criteria); for these specific analyses using the restricted definition, individuals with onset of DSM-IV alcohol dependence at age 25 years or greater were coded as unknown.…”

Plasma Homovanillic Acid: A Significant Association with Alcoholism is Independent of a Functional Polymorphism of the Human Catechol-O-Methyltransferase Gene

“…A genetic polymorphism results in three-to four-fold differences in COMT activity (Grossman et al, 1992). Studies that tried to associate the low activity (L) allele of COMT with alcoholism revealed contradictory results Tiihonen et al, 1999;Ishiguro et al, 1999;Wang et al, 2001). Men with the LL genotype have shown a significantly higher weekly alcohol consumption than individuals with other genotypes .…”