Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In recent years, it has become increasingly evident that there is a genetic component to alcoholism. Attempts to isolate alcoholism genes have met with modest success, in part because alcoholism is a multigenic trait. Recently, experimental animal models and novel genetic manipulations have provided several clues as to the specific genes involved in alcoholism, and extensive research has identified many genes that might influence responses to alcohol. Although not all of these might be proven to influence drug sensitivity, research has provided evidence for the involvement of a few genes. Ultimately, findings from animal models that investigate the function of specific genes could aid the development of pharmacotherapies to treat alcohol dependence.
Mol Med Today 1999 Jul
PMID:Alcohol and genetics: new animal models. 1037 23

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, may contribute to the etiology of mental disorders such as bipolar disorder and alcoholism. Since ethanol-induced euphoria is associated with the rapid release of dopamine 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 development 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 polymorphism contributes significantly to the development of late-onset alcoholism.
Mol Psychiatry 1999 May
PMID:Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism. 1039 22

A common 44-base pair insertion/deletion polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been observed to be associated with affective illness and anxiety-related traits. This biallelic functional polymorphism, designated long (L) and short (S), affects 5-HTT gene expression since the S promoter is less active than the L promoter. Since there is strong evidence of a disturbance in brain serotonergic transmission among antisocial, impulsive, and violent type 2 alcoholic subjects, we decided to test the hypothesis that the frequency of the S allele, which is associated with reduced 5-HTT gene expression, is higher among habitually violent type 2 alcoholics when compared with race and gender-matched healthy controls and non-violent late-onset (type 1) alcoholics. The 5-HTT promoter genotype was determined by a PCR-based method in 114 late onset (type 1) non-violent alcoholics, 51 impulsive violent recidivistic offenders with early onset alcoholism (type 2), and 54 healthy controls. All index subjects and controls were white Caucasian males of Finnish origin. The S allele frequency was higher among type 2 alcoholics compared with type 1 alcoholics (chi2 = 4.86, P = 0.028) and healthy controls (chi2 = 8.24, P = 0.004). The odds ratio for SS genotype vs LL genotype was 3.90, 95% Cl 1.37-11.11, P = 0.011 when type 2 alcoholics were compared with healthy controls. The results suggest that the 5-HTT 'S' promoter polymorphism is associated with an increased risk for early onset alcoholism associated with antisocial personality disorder and impulsive, habitually violent behavior.
Mol Psychiatry 1999 Jul
PMID:Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. 1048 57

A role for the GABA/benzodiazepine receptor complex in alcohol dependence syndrome has been suggested by several lines of evidence. To elucidate the role of GABAA subunits in human alcohol dependence syndrome, we identified polymorphisms in the GABAAbeta2 and GABAAalpha6 receptor subunit genes on 5q33 and assessed their potential contribution in an association study, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene. One hundred and eight alcohol-dependent subjects and 54 unrelated controls were recruited from Scotland. Two novel genetic markers were identified at the GABAAbeta2 and GABAAalpha6 receptor subunit genes and examined for association with the alcohol dependence syndrome and subgroups of subjects with Korsakoff's psychosis and without Korsakoff's psychosis, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene. The chi2 tests demonstrated associations between all alcohol-dependent subjects (not stratified) and the BanI RFLP at the GABAAbeta2 receptor subunit gene (P = 0.015), and the AlwNI RFLP at the GABAAalpha6 receptor gene (P = 0.013). Significant associations were also found between the alcohol-dependent subjects with Korsakoff's psychosis and the BanI RFLP (P = 0.039) and the AlwNI RFLP (P = 0.003). Haplotype analysis also provided evidence of association when all alcohol-dependent subjects (P = 0.013) and the subjects with Korsakoff's psychosis (P = 0.007) were compared with controls. Our findings provide evidence for a role for the GABAA receptor subunit cluster on chromosome 5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's psychosis.
Mol Psychiatry 1999 Nov
PMID:Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population. 1057 35

Human dopamine transporter gene (DAT1) has a variable number of tandem repeats (VNTR) in its 3'-untranslated region (UTR). The association between the VNTR polymorphism and neuropsychiatric disorders has been studied, but their relationship is still unclear. Here we identified a novel polymorphism in the 3'-UTR of the DAT1 gene, G2319A, and a significant association between the polymorphism and alcoholism was observed in both genotypic and allelic frequencies (P = 0.040 and 0.019, extended Fisher's exact test, respectively). There was a significant gene dose effect on the risk for alcoholism associated with the 2319-A allele (chi2 = 6.16, df = 2, P = 0.046, linearity tendency test: Cochranq-Armitage analysis). Moreover, in the haplotype analysis with G2319A- and VNTR-polymorphisms, a positive gene dose efffect on the risk with the A10 allele (P = 0.044, linearity tendency test) and a negative gene dose effect with the G10 allele (P = 0.010, linearity tendency test) for alcoholism were significantly detected. Odds ratio for alcoholism with the A10 and G10 alleles were 1.76 (1.12-2.76) and 0.53 (0.32-0.79), respectively. These results indicate that the DAT1 gene may confer vulnerability to alcoholism.
Mol Psychiatry 1999 Nov
PMID:Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism. 1057 37

Gamma-aminobutryic acid (GABA) is a major neurotransmitter in the central nervous system, and plasma levels of GABA may reflect brain GABA activity. In 35-40% of patients with mood disorders, plasma GABA levels are low compared to psychiatrically normal controls. Low plasma GABA in this subgroup of patients has characteristics of a biological trait marker for mood disorders. Low plasma GABA is also found in a subset of patients with alcohol dependence, but not in schizophrenia, anxiety, or eating disorders, suggesting some diagnostic specificity. Previous data from a small study of monozygotic twins are consistent with the hypothesis that plasma GABA levels are under genetic control. To better understand these mechanisms, we conducted a segregation analysis of plasma GABA levels in a sample of 157 individuals from 50 nuclear families. Analysis using the Class D regressive model indicated that the familial transmission of plasma GABA levels is compatible with the segregation of a recessive major gene. Our results suggest that plasma GABA levels are under single gene control. Future research should address the precise mechanisms which may account for the abnormality in GABA levels seen in a subset of patients with mood disorders.
Mol Psychiatry 1999 Nov
PMID:Evidence for the segregation of a major gene for human plasma GABA levels. 1057 42

This review focuses on the regulation of the mammalian medium-chain alcohol dehydrogenase (ADH) genes. This family of genes encodes enzymes involved in the reversible oxidation of alcohols to aldehydes. Interest in these enzymes is increased because of their role in the metabolism of beverage alcohol as well as retinol, and their influence on the risk for alcoholism. There are six known classes ADH genes that evolved from a common ancestor. ADH genes differ in their patterns of expression: most are expressed in overlapping tissue-specific patterns, but class III ADH genes are expressed ubiquitously. All have proximal promoters with multiple cis-acting elements. These elements, and the transcription factors that can interact with them, are being defined. Subtle differences in sequence can affect affinity for these factors, and thereby influence the expression of the genes. This provides an interesting system in which to examine the evolution of tissue specificity. Among transcription factors that are important in multiple members of this gene family are the C/EBPs, Sp1,USF, and AP1, HNF-1, CTF/NF-1, glucocorticoid, and retinoic acid receptors, and several as-yet unidentified negative elements, are important in at least one of the genes. There is evidence that cis-acting elements located far from the proximal promoter are necessary for proper expression. Three of the genes have upstream AUGs in the 5' nontranslated regions of their mRNA, unusual for mammalian genes. The upstream AUGs have been shown to significantly affect expression of the human ADH5 gene.
Prog Nucleic Acid Res Mol Biol 2000
PMID:Regulation of the mammalian alcohol dehydrogenase genes. 1069 13

The reputation of the field of psychiatric genetics has recently become tarnished in the view of many human geneticists. Too many linked loci were claimed and withdrawn, too many association studies published and not confirmed and, more recently, too many new and different chromosomal regions have been implicated for the same disorder. Here, we summarize recent trends, focusing on research that moves away from traditional linkage studies. Some promising strategies include psychopharmacogenetics, and consideration of endophenotypes such as neurophysiological and behavioral markers in addition to the clinical diagnosis. Utilization of rapid and automated methods for scoring genetic variants in large-scale association studies followed by multivariate analyses, which include environmental as well as genetic data, will likely fare better than traditional linkage analysis in disentangling the complex genetics of psychiatric disorders. Some notable areas of recent progress include quantification of the genetic complexity of autism, identification of genetic variants protecting individuals from alcoholism, and the description of several polymorphisms likely to be relevant to behavior and psychiatry. The most notable example may be a common variant that affects the transcription rate in the promoter for the serotonin transporter gene that may be relevant for individual differences in the response to common anti-depressants.
Hum Mol Genet 2000 Apr 12
PMID:Recent progress in psychiatric genetics-some hope but no hype. 1076 16

There is abundant evidence that the serotonin (5-HT) system is modulating mood and several behavioural traits and that disturbances in the regulation of this system can be associated with severe behavioural malfunctions, as aggressive implusive and suicidal behaviour.1 Recently a functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was identified2 and the presence of one or two short alleles was associated with anxiety-related personality traits3 and several psychiatric disturbances, such as affective disorder4 or severe alcohol dependence.5 With respect to the importance of the 5-HT transporter in serotonergic transmission, we have genotyped the DNA of 58 Caucasian suicide victims (with unknown psychiatric diagnoses) and 110 healthy controls for the biallelic functional polymorphism in the 5-HTTLPR. We found a highly significant increased frequency of suicide victims being carriers of one or two short alleles (Fisher's Exact Test, two sided, P = 0.0003), which suggests that a genetically altered protein function within the serotonergic pathway might be involved in suicidality, independently from the clinical diagnosis.
Mol Psychiatry 2000 Mar
PMID:Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide. 1131 12

Recent investigations suggest that genetic susceptibility to alcohol dependence may be conferred by GABA(A) receptor subunit genes. In this study, three RFLPs at the GABA(A)beta2, GABAAalpha6, GABA(A)alpha1 and two at the GABA(A)gamma2 receptor subunit genes, were examined for association with alcohol dependence in 189 subjects meeting DSM-III-R criteria for this disorder and 152 unrelated controls from a Japanese population. The results demonstrated no association between the AlwNI RFLP at the GABA(A)alpha6 receptor subunit gene and alcohol dependence (P = 0.059). However, the NciI RFLP at the GABA(A)gamma2 receptor subunit gene was associated with alcohol dependence comorbid with antisocial personality disorder (P = 0.021). This supports a recent finding reporting an association between the GABA(A)gamma2 receptor subunit gene and alcohol dependence with criminal record in a Finnish population. Taking into account the effects of multiple comparisons, this result should be interpreted with caution pending replication.
Mol Psychiatry 2000 May
PMID:Association analysis of the GABA(A) receptor subunit genes cluster on 5q33-34 and alcohol dependence in a Japanese population. 1088 33


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