Molecular Psychiatry (1999) 4, 286–289  1999 Stockton Press All rights reserved 1359–4184/99 $12.00 ORIGINAL RESEARCH ARTICLE Association between the functional variant of the catechol-O- methyltransferase (COMT) gene and type 1 alcoholism J Tiihonen 1,2 , T Hallikainen 1 , H Lachman 3 , T Saito 3 , J Volavka 4 , J Kauhanen 5,6 , JT Salonen 5,6 , O-P Ryyna ¨nen 5 , M Koulu 7 , MK Karvonen 7 , T Pohjalainen 7 , E Syva ¨ lahti 7 and J Hietala 8 1 Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, Kuopio, Finland; 2 Department of Clinical Physiology, Kuopio University Hospital, Kuopio, Finland; 3 Albert Einstein College of Medicine, New York, USA; 4 Nathan Kline Institute, Orangeburg, New York, USA; 5 Department of Public Health and General Practice, University of Kuopio, Kuopio, Finland; 6 Research Institute of Public Health, University of Kuopio, Kuopio, Finland; 7 Department of Pharmacology, University of Turku, Turku, Finland; 8 Department of Psychiatry, Turku University Central Hospital, Turku, Finland Keywords: alcoholism; catechol-O-methyltransferase; COMT; polymorphism; dopamine; substance-abuse dis- orders Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopamine. It has been suggested that a common functional genetic polymorphism in the COMT gene, which results in 3 to 4-fold difference in COMT enzyme activity, 1,2 may con- tribute to the etiology of mental disorders such as bipolar disorder and alcoholism. 1 Since ethanol-induced euphoria is associated with the rapid release of dopa- mine in limbic areas, it is conceivable that subjects who inherit the allele encoding the low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the develop- ment of ethanol dependence. The aim of this study was to test this hypothesis among type 1 (late-onset) alcoholics. The COMT polymorphism was determined in two independent male late onset (type 1) alcoholic populations in Turku (n = 67) and Kuopio (n = 56). The high (H) and low (L) activity COMT genotype and allele frequencies were compared with previously published data from 3140 Finnish blood donors (general population) and 267 race- and gender-matched controls. The frequency of low activity allele (L) was markedly higher among the patients both in Turku (P = 0.023) and in Kuopio (P = 0.005) when compared with the general population. When all patients were compared with the general population (blood donors), the difference was even more significant (P = 0.0004). When genotypes of all alcoholics (n = 123) were compared with genotypes of matched controls, the odds ratio (OR) for alcoholism for those subjects having the LL genotype vs those with HH genotype was 2.51, 95% CI 1.22–5.19, P = 0.006. Also, L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiological (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI 2.3–25.7%). The results indicate that the COMT polymor- phism contributes significantly to the development of late-onset alcoholism. Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopa- mine. A common functional polymorphism in the COMT gene is responsible for enzyme activity varia- bility found in the general population. It has been sug- gested that this genetic polymorphism may contribute to the etiology of mental disorders such as schizo- phrenia, obsessive compulsive disorder (OCD) and alcoholism. 1 There is solid evidence that a G → A tran- sition at COMT codon 158 is associated with three- to four-fold variation in COMT enzyme activity in human hepatic tissue and red blood cells. 1,2 Homozygosity for the high activity allele (HH genotype) is found in approximately 25% of Caucasians. Homozygosity for the low activity allele (LL genotype) is also found in approximately 25% of Caucasians. Heterozygotes (LH genotype) have intermediate levels of COMT activity. 1,2 Thus far empirical evidence for an association between the COMT L allele and mental disorders has been reported in patients with velo-cardio-facial syndrome (VCFS), 3 rapid cycling bipolar disorder, 4,5 schizo- phrenia and schizoaffective disorder with increased violent behavior, 6,7 and in patients with OCD. 8 On the other hand, some studies have failed to show any association between COMT polymorphism and schizo- phrenia or affective disorders. 9–12 In addition, Li et al 13 reported an association between COMT H allele and schizophrenia rather than transmission of the L allele. Alcoholism has been classified into two subgroups, type 1 and type 2. 14 Type 2 alcoholism is associated with early onset, high novelty seeking and impulsive antisocial behavior. The majority of alcoholics can be classified as type 1, which is characterized by late onset (over 25 years) and no prominent antisocial behavior. 14 In vivo brain imaging studies in humans have indicated that a dysfunction in dopaminergic neurotransmission occurs in type 1 alcoholics 15–18 but not in type 2 alcoholics. 17 Since ethanol-induced euphoria is associated with the rapid release of dopa- mine in limbic areas, 19 it is logical to assume that those subjects having the low activity COMT allele— resulting in low dopamine inactivation rate—would be more vulnerable to the development of ethanol depen- dence than those having the high activity COMT allele. The COMT genotype and allele frequencies are shown in Table 1. The COMT genotypic distributions were in Hardy–Weinberg equilibrium in both patients and controls. The L allele frequency was higher among the patients both in Turku ( 2 = 5.21, P = 0.023) and in Kuopio ( 2 = 8.03, P = 0.005) when compared with