ALCOHOL DEPENDENCEUpdated January 16. 2007
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#103780 ALCOHOL DEPENDENCE
Alternative titles; symbols
ALCOHOLISM
Gene map locus 13q14-q21, 4q22, 4p13-p12
TEXT
A number sign (#) is used with this entry because of the demonstrated role of multiple genes in determining the genetic susceptibility for alcoholism that is supported by family, twin, and other studies.
INHERITANCE
The tendency for drinking patterns of children to resemble those of their parents has been recognized since antiquity, e.g., in the observations of Plato and Aristotle (Warner and Rosett, 1975). Alcoholism is probably a multifactorial, genetically influenced disorder (Goodwin, 1976). The genetic influence is indicated by studies showing that (1) there is a 25 to 50% lifetime risk for alcoholism in sons and brothers of severely alcoholic men; (2) alcohol preference can be selectively bred for in experimental animals; (3) there is a 55% or higher concordance rate in monozygotic twins with only a 28% rate for like-sex dizygotic twins; and (4) half brothers with different fathers and adopted sons of alcoholic men show a rate of alcoholism more like that of the biologic father than that of the foster father. A possible biochemical basis is a metabolic difference such that those prone to alcoholism have higher levels of a metabolite giving pleasurable effects or those not prone to alcoholism have higher levels of a metabolite giving unpleasant effects. Schuckit and Rayses (1979) found that, after a moderate dose of alcohol, blood acetaldehyde levels were elevated more in young men with alcoholic parents or sibs than in controls. A certain degree of organ specificity in the pathologic effects of alcohol is observed. For example, patients have cardiomyopathy, cirrhosis, or pancreatitis but rarely more than one of these. A genetic basis of organ specificity is evident in Wernicke-Korsakoff syndrome (277730) and pancreatitis from type V hyperlipidemia (238400).
Cloninger (1987) identified 2 separate heritable types of alcoholism. Type 1 alcohol abuse had its usual onset after the age of 25 years and was characterized by severe psychological dependence and guilt. It occurred in both men and women and required both genetic and environmental factors to become manifest. By contrast, type 2 alcohol abuse had its onset before the age of 25; persons with this type of alcoholism were characterized by their inability to abstain from alcohol and by frequent aggressive and antisocial behavior. Type 2 alcoholism was rarely found in women and was much more heritable. Abnormalities in platelet monoamine oxidase activity were found only in type 2 alcoholics (Von Knorring et al., 1985). See comments by Omenn (1988). 
Crabb (1990) reviewed biologic markers for increased risk of alcoholism. Aston and Hill (1990) performed complex segregation analysis of 35 multigenerational families ascertained through a pair of male alcoholics. They concluded that liability to alcoholism is, in part, controlled by a major effect with or without additional multifactorial effects. However, mendelian transmission of this major effect was rejected, as was the hypothesis that the major effect is due to a single major locus.
In connection with a collection of 11 research reports on the genetics of alcohol-related traits, Buck (1998) gave a brief review on recent progress toward the identification of genes related to risk for alcoholism.
MAPPING
Nurnberger et al. (2001) reported linkage data indicating that a susceptibility locus for alcoholism and/or depression phenotypes resides on chromosome 1p. Using short tandem repeat (STR) markers and the transmission disequilibrium test in 87 European-American families with one or more alcohol-dependent offspring (93 children and 174 parents), Lappalainen et al. (2004) fine-mapped the region identified by Nurnberger et al. (2001). The strongest evidence for transmission disequilibrium was for marker D1S406 (p = 0.005). Three other markers, all within less than 350 kb, had supporting evidence for transmission disequilibrium: D1S424 (p = 0.01), D1S2804 (p = 0.04), and D1S2776 (p = 0.02). Lappalainen et al. (2004) suggested that one or more genes causing susceptibility to alcohol dependence reside on chromosome 1 in a region approximately delimited by markers D1S1170 and D1S2779.
Event-related brain potentials (ERPs) are recordings of neuroelectric activity, usually in response to some task, made from electrodes on the scalp. ERPs are altered in patients with a variety of psychiatric disorders and in members of their families, compared with the general population. Alcoholic subjects have a reduction of amplitude of the P3 component, a positive peak approximately 300-600 ms after a stimulus, that remains after long periods of abstinence from alcohol (Porjesz and Begleiter, 1985). A similar reduction in P3 amplitude is also seen in young alcohol-naive sons of alcoholic probands (Begleiter et al., 1984). Almasy et al. (2001) presented results of a genomewide linkage screen for amplitude of the N4 and P3 components of the ERP, measured at 19 scalp locations in response to a semantic priming task for 604 individuals in 100 pedigrees ascertained as part of a collaborative study on the genetics of alcoholism. N4 and P3 amplitudes in response to 3 semantic stimuli showed significant heritabilities, the highest being 0.54. Both N4 and P3 amplitudes showed significant genetic correlations across stimulus type at a given lead and across leads within a stimulus, indicating shared genetic influences among the traits. N4 amplitudes showed suggestive evidence of linkage in several chromosomal regions, and P3 amplitudes showed significant evidence of linkage to chromosome 5 and suggestive evidence of linkage to chromosome 4.
Ehlers et al. (2004) used a panel of 791 microsatellite polymorphisms to map susceptibility loci for DSM-III-R alcohol dependence and 2 narrower alcohol-related phenotypes (alcohol use severity phenotype and withdrawal phenotype) in Mission Indian families (466 individuals). Analyses of multipoint variance component lod scores for the dichotomous DSM-III-R phenotype revealed no peak lod scores that exceeded 2.0. For the alcohol use severity phenotype, chromosomes 4 and 12 had peak lod scores that exceeded 2.0, and for the withdrawal phenotype, chromosomes 6, 15, and 16 were found to have peak lod scores that exceeded 2.0. Combined linkage and association analyses suggested that polymorphisms of the alcohol dehydrogenase-1B gene (ALD2; 103720) were partially responsible for the linkage result on chromosome 4 in this population.
Prescott et al. (2006) conducted a genome scan in the Irish Affected Sib Pairs Study of Alcohol Dependence sample set. Most of the probands were ascertained through alcoholism treatment settings and were severely affected. Probands, affected sibs, and parents were evaluated by structured interview. Most of the 474 families in the study were comprised of affected sib pairs (96%). Quantitative results indicated strong linkage for alcohol dependence criteria (defined by DSM IV) to chromosome 4q22-4q32 (peak multipoint lod = 4.59, p = 0.0000021 at D4S1611).
Hill et al. (2004) studied families containing alcoholics (330 individuals) identified through a double proband methodology. Multipoint linkage analyses using 360 markers for 22 autosomes gave strong support for loci on chromosomes 1, 2, 6, 7, 10, 12, 14, 16, and 17.
MOLECULAR GENETICS
Association with the ADH Gene Cluster on Chromosome 4q22
Chai et al. (2005) examined polymorphisms in the ADH2 (103720) and ADH3 (103730) genes on chromosome 4q22 and in the ALDH2 (100650) gene on chromosome 12q24 in 72 alcoholic and 38 nonalcoholic healthy Korean men. Forty-eight of the alcoholic men had Cloninger type 1 and 24 had Cloninger type 2 alcoholism. The frequency of ADH2*1 (103720.0001) and ADH3*2 (103730.0002) alleles was significantly higher in men with type 2 alcoholism than in men with type 1 alcoholism and in healthy men. The frequency of the ALDH2*1 (100650.0001) allele was significantly higher in men with alcohol dependence than in healthy men. Chai et al. (2005) suggested that the genetic characteristics of alcohol metabolism in type 1 alcoholism fall between nonalcoholism and type 2 alcoholism.
Association with the GABA-A Receptor Gene Cluster on Chromosome 5q34
Radel et al. (2005) genotyped a Southwestern Native American sample of 433 individuals and a Finnish sample of 511 individuals, including both alcohol-dependent and unaffected individuals, for 6 SNPs in the GABA-A receptor gene cluster (see 137140) on chromosome 5q34. Sib-pair linkage and case-control association analyses as well as linkage disequilibrium mapping with haplotypes were done. Radel et al. (2005) detected sib-pair linkage of 5q34 GABA-A receptor genes to alcohol dependence in both population samples. Haplotype localization implicated 3 polymorphisms of GABRA6 (137143), including a pro385-to-ser substitution.
Association with the NPY Gene on Chromosome 7p15
Kauhanen et al. (2000) and Lappalainen et al. (2002) found an association between susceptibility to alcoholism and a leu7-to-pro polymorphism in the neuropeptide Y (NPY) gene on chromosome 7p15; see 162640.0001.
Association with the TAS2R16 Gene on Chromosome 7q31
Hinrichs et al. (2006) found a functional variant in a bitter-taste receptor (TAS2R16; 604867.0001) on chromosome 7q31 that influences risk of alcohol dependence. The K172 allele of the K172N SNP showed an increased risk of alcohol dependence, regardless of ethnicity. However, this risk allele was uncommon in European Americans, whereas 45% of African Americans carried the K172 allele, which makes this a much more significant risk factor in that population.
Association with the CHRM2 Gene on Chromosome 7q35
Genomewide linkage analyses using pedigrees from the Collaborative Study of the Genetics of Alcoholism (COGA) provided consistent evidence of an alcoholism susceptibility locus on the long arm of chromosome 7 (Reich et al., 1998; Foroud et al., 2000).
By fine mapping of 488 sib pairs with alcohol dependence, Wang et al. (2004) refined the locus on chromosome 7q to D7S1799 (lod = 2.9). They examined 11 SNPs within and flanking the CHRM2 gene (118493) in 262 families with alcohol dependence from the COGA. Three SNPs showed highly significant association with alcoholism (p = 0.004, 0.004, and 0.007, respectively). Two SNPs were significantly associated with major depressive syndrome (MDD; 608516) (p = 0.004 and 0.017). Haplotype analyses revealed that the most common haplotype, T-T-T (rs1824024, rs2061174, and rs324650), was undertransmitted to affected individuals with alcohol dependence and major depressive syndrome.
Association with the DRD2 Gene on Chromosome 11q23
The candidate gene approach was used by Blum et al. (1990) and by Bolos et al. (1990) to investigate a possible relationship of the dopamine D2 receptor (DRD2; 126450), which maps to chromosome 11q23, to alcoholism. Although Blum et al. (1990) suggested an association between a particular allele at the DRD2 locus, Bolos et al. (1990) could not confirm this. In family studies, Bolos et al. (1990) excluded linkage between alcoholism and the DRD2 locus.
Johann et al. (2005) studied the association of a -141C deletion variant (-141delC) of the DRD2 gene in 1,126 well-characterized, primary chronic alcoholics of German descent according to a phenotype-genotype strategy and found an excess of the -141delC alleles in alcoholics with a paternal and grandpaternal history of alcoholism and in alcoholic subgroups with suicidality or without a history of withdrawal symptoms. Johann et al. (2005) concluded that the -141delC variant of DRD2 might be a protective factor against the development of withdrawal symptoms but might also be a risk factor in a highly burdened subgroup of alcoholics with a paternal and grandpaternal history of alcoholism and might contribute to suicide risk in alcoholics.
Association with the ALDH2 Gene on Chromosome 12
Chai et al. (2005) examined polymorphisms in the ADH2 and ADH3 genes on chromosome 4q22 and in the ALDH2 (100650) gene on chromosome 12q24 in 72 alcoholic and 38 nonalcoholic healthy Korean men. Forty-eight of the alcoholic men had Cloninger type 1 and 24 had Cloninger type 2 alcoholism. The frequency of the ALDH2*1 (100650.0001) allele was significantly higher in men with alcohol dependence than in healthy men. Also see 'Association with the ADH Gene Cluster on Chromosome 4q22.'
Association with the ANKK1 Gene (TaqIA Allele) on Chromosome 11q23
In a study of the TaqIA polymorphism (see ANKK1; 608774) in 884 nonalcoholic Finnish Caucasian males, Hallikainen et al. (2003) found that the self-reported alcohol consumption of the homozygous A1/A1 group was 30% and 40% lower than that of the A1/A2 and A2/A2 groups, respectively (p = 0.042).
Association with the SLC6A4 Gene on Chromosome 17q
Feinn et al. (2005) conducted a metaanalysis of the association of the functional serotonin transporter promoter polymorphism (SLC6A4; 182138.0001) on chromosome 17q with alcohol dependence. The metaanalysis was from data collected from 17 published studies including 3,489 alcoholics and 2,325 controls. The frequency of the short allele was significantly associated with alcohol dependence (OR = 1.18, 95% CI = 1.03-1.33). A greater association with the S allele was seen among individuals with alcohol dependence complicated by either a comorbid psychiatric condition or an early-onset or more severe alcoholism subtype (OR = 1.34, 95% CI = 1.11-1.63).
Following up on a study by Herman et al. (2003) that showed an association between the SLC6A4 short form of the promoter polymorphism and alcohol consumption in a college population, Munafo et al. (2005) studied 755 individuals, aged 33 to 73 years, who were recruited from general practices in the U.K. as part of a study of genetic associations with smoking cessation. Subjects were assessed for age, gender, body mass index, weekly alcohol consumption, ethnicity, and smoking habits. Individuals who were nondrinkers were excluded from the study. Genotyping was done for SLC6A4 long and short promoter polymorphisms. The short allele was significantly associated with increased alcohol consumption (p = 0.03). There was suggestive evidence of a genotype-sex interaction (p = 0.04). Post hoc analysis indicated higher alcohol consumption in men with one or more copies of the short allele, whereas consumption in women was highest among heterozygotes compared to both homozygote groups.
Association with the COMT Gene on Chromosome 22q11
The enzyme catechol-O-methyltransferase (COMT; 116790), encoded by a gene on chromosome 22q11, has a crucial role in the metabolism of dopamine. Lachman et al. (1996) 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 was considered conceivable that subjects who inherited 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. In 2 Finnish populations of type 1 (late-onset) alcoholics, Tiihonen et al. (1999) found a markedly higher frequency of the low activity allele (L). They estimated that the population etiologic (attributable) fraction for the LL genotype in alcoholism was as high as 13.3%.
ANIMAL MODEL
Liang et al. (2003) demonstrated that in alcohol-preferring and alcohol-nonpreferring rats, a polymorphism in the alpha-synuclein gene (SNCA; 163890) maps to the same location as a QTL for alcohol preference.
