Alcohol Dependence

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. See MOLECULAR GENETICS.

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 (144650).

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.

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 (ADH1B; 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.

By genomewide ordered subset linkage analysis for alcohol dependence using admixture proportion as a covariate among African Americans, Han et al. (2013) found significant linkage to a locus on chromosome 4q (maximum lod score of 4.2) in a subset of 44 families with an African ancestry proportion ranging from 0.858 to 0.996. The candidate region includes the GLRA3 gene (600421), which encodes a subunit of the glycine neurotransmitter receptor. A second genomewide significant linkage result was observed on chromosome 22 (lod of 3.23) in a subset of 33 families with a high proportion of African ancestry ranging from 0.885 to 0.996.

Han et al. (2013) aimed to integrate genomewide association studies (GWASs) and human protein interaction networks to investigate whether a subnetwork of genes whose protein products interact with each other might collectively contribute to alcohol dependence. By using 2 discovery GWAS datasets of the Study of Addiction: Genetics and Environment (SAGE) and the Collaborative Study on the Genetics of Alcoholism (COGA), Han et al. (2013) identified a subnetwork of 39 genes that not only was enriched for genes associated with alcohol dependence, but also collectively associated with alcohol dependence in both European Americans (p less than 0.0001) and African Americans (p = 0.0008). Han et al. (2013) replicated the association of the gene subnetwork with alcohol dependence in 3 independent samples, including 2 samples of European descent (p = 0.001 and p = 0.006) and 1 sample of African descent (p = 0.0069). To evaluate whether the significant associations were likely to be false-positive findings and to ascertain their specificity, Han et al. (2013) examined the same gene subnetwork in 3 other human complex disorders (bipolar disorder, major depressive disorder, and type 2 diabetes) and found no significant associations. Functional enrichment analysis revealed that the gene subnetwork was enriched for genes involved in cation transport, synaptic transmission, and transmission of nerve impulses, all of which are biologically meaningful processes that may underlie the risk for alcohol dependence.

Kim et al. (2015) showed that GABA corelease in midbrain dopamine neurons is mediated by aldehyde dehydrogenase 1a1 (ALDH1A1; 100640) in an evolutionarily conserved GABA synthesis pathway. GABA corelease is modulated by ethanol at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1A1 leads to enhanced alcohol consumption and preference. Kim et al. (2015) concluded that their findings provided insights into the functional role of GABA corelease in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.

George et al. (2008) investigated the role of the neurokinin-1 receptor (NK1R, or TACR1; 162323), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, George et al. (2008) treated recently detoxified alcoholic inpatients with an NK1R antagonist (n = 25) or placebo (n = 25). The NK1R antagonist suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial NK1R antagonist effects. George et al. (2008) suggested that given these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.

Flatscher-Bader et al. (2008) compared gene expression analysis of postmortem brain tissue from the ventral tegmental area (VTA) of 6 chronic alcoholics and 6 controls. Stringent analysis identified changes affecting 3 distinct functional themes between the 2 groups: neuron function, cell signaling, and alcohol and glucose metabolism. Genes involved in morphologic plasticity were identified in a less stringent analysis.

Association with the ADH Gene Cluster on Chromosome 4q22

In a genomewide linkage study in families mostly of European ancestry, Reich et al. (1998) found evidence that supported the genetic linkage between alcoholism and the region of chromosome 4 that includes the ADH genes. In a sample of an Amerindian population, Long et al. (1998) found evidence that supported the genetic linkage between alcohol dependence and a nearby region on chromosome 4.

Chai et al. (2005) examined polymorphisms in the ADH2 (ADH1B; 103720) and ADH3 (ADH1C; 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 ADH1B*1 (see 103720.0001) and ADH1C*2 (see 103730.0001) 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.

Edenberg et al. (2006) found an association between alcohol dependence and several SNPs in the ADH4 gene (103740). The SNP showing the greatest evidence of association (rs4148886) yielded a p value of 0.0042; permutation testing resulted in a global significance of 0.036. The region of strongest association (p = 0.01) ran from intron 1 to 19.5-kb beyond the ADH4 gene into the intergenic region between ADH4 and ADH5 (103710).

Using data on in vivo alcohol metabolism obtained from 206 Australian twin pairs of Caucasian ancestry, Birley et al. (2008) found an association between SNPs and haplotypes in the ADH7 gene (600086) and interindividual variation in the early stages of alcohol metabolism. The patterns of linkage disequilibrium among these SNPs identified a recombinational hotspot within a 35-kb DNA tract contained in the region 5-prime to intron 7 in the ADH7 gene. The region accounted for 18% of the linkage for alcohol concentration associated with the ADH region, or approximately 11% of the genetic variance.

Among 9,080 Caucasian Danish men and women, Tolstrup et al. (2008) found that those with genotypes encoding slow alcohol metabolism ADH1B*1 (see 103720.0001) and ADH1C*2 (see 103730.0001) drank more alcohol and had higher risks of alcoholism compared to those with genotypes encoding faster alcohol metabolism. Effect sizes were smaller for the ADH1C genotype than for the ADH1B genotype. Since slow ADH1B alcohol degradation (arg48) is found in more than 90% of the white population compared to less than 10% of East Asians, the population attributable risk of heavy drinking and alcoholism by the ADH1B arg48/arg48 genotype was 67 and 62% among the white population compared with 9 and 24% among the East Asian population.

In 206 Australian twin pairs, 216 parents, and 226 nontwin sibs, Birley et al. (2009) genotyped 103 SNPs across the ADH gene cluster region to test for allelic associations with variation in blood and breath alcohol concentrations after an alcohol challenge. In vivo alcohol metabolism was modeled with 3 parameters that identified the absorption and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were strongly associated (p less than 0.001; rs1154461, rs1154468, rs1154470, and rs894363) with the early stages of alcohol metabolism, with additional effects seen for SNPs in the ADH1A, ADH1B, and ADH4 (103740) regions. Rate of elimination was associated with multiple SNPs in the intragenic region between ADH7 and ADH1C, and across ADH1C and ADH1B. SNPs affecting alcohol metabolism did not correspond to those reported to affect alcohol dependence or alcohol-related disease. The combined SNP associations with early- and late-stage metabolism only accounted for approximately 20% of the total genetic variance linked to the ADH region, and most of the variance for in vivo alcohol metabolism linked to this region is yet to be explained.

Macgregor et al. (2009) tested for associations between 9 polymorphisms in the ALDH2 gene and 41 in the ADH genes, and alcohol-related flushing, alcohol use, and dependence symptom scores in 4,597 Australian twins, predominantly of European ancestry. The vast majority (4,296 individuals) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for alcohol dependence. There were study-wide significant associations between rs1229984 (103720.0001) and flushing and consumption, but only nominally significant associations (p less than 0.01) with alcohol dependence. Individuals carrying the G allele/arg48 reported a lower prevalence of flushing after alcohol, consumed alcohol on more occasions, had a higher maximum number of alcoholic drinks in a single day and a higher overall alcohol consumption in the previous year than those with the less common A allele/his48. After controlling for rs1229984, an independent association was observed between rs1042026 in the ADH1B gene and alcohol intake and suggestive associations between alcohol consumption phenotypes and rs1693482 in the ADH1C gene (see 103730.0001), rs1230165 (ADH5; 103710) and rs3762894 (ADH4; 103740). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with alcohol dependence measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B R48H polymorphism affects both alcohol-related flushing in Europeans and alcohol intake.

See 103720.0001 for discussion of a possible association between protection against alcohol-related aerodigestive tract cancer and variation in the ALDH1B gene.

Association with the SNCA gene on Chromosome 4q22.1

Bonsch et al. (2005) found an association between the length of the SNCA REP1 allele and alcohol dependence in 135 Caucasian alcoholic patients and 101 healthy Caucasian controls. The longer 273- and 271-bp alleles were more frequent in alcoholic patients compared to controls (p less than 0.001), and higher SNCA mRNA expression levels were correlated with the longer SNCA REP1 alleles.

Association with the DKK2 gene on Chromosome 4q25

Kalsi et al. (2010) conducted a systematic, gene-centric association study of alcohol dependence using 518 SNPs within the 65 genes of the linkage peak on chromosome 4q21-q32 identified by Prescott et al. (2006). Case-only regression analysis with the quantitative variable of alcohol-dependent symptoms was performed in 562 genetically independent cases of the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample. Gene-wise correction for multiple testing yielded empirical evidence of association with 3 SNPs in DKK2 in the cohort (rs427983, rs419558, rs399087; p less than 0.007). The association was replicated in 847 cases of European descent from a large independent sample, the Collaborative Study of the Genetics of Alcoholism (COGA). Haplotype-specific expression measurements in postmortem tissue samples suggested a functional role for DKK2.

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, the TAS2R16 gene (604867) on chromosome 7q31, that influences risk of alcohol dependence. The lys172 allele of the K172N SNP (604867.0001) 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 lys172 allele, which makes this a much more significant risk factor in the African American population.

Association with the TAS2R38 Gene on Chromosome 7q35

In a study of 2,309 individuals from 262 families with alcohol dependence comprising both European American and African American individuals (the same cohort as studied by Hinrichs et al., 2006), Wang et al. (2007) found an association between the nontaster haplotype in the TAS2R38 gene (607751) and maximum alcohol consumption only among African American females. The taster haplotype was associated with lower maximum alcohol consumption (p = 0.035). However, there was no evidence that TAS2R38 haplotypes influence alcohol dependence.

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.

Luo et al. (2005) examined the relationships between variation in the CHRM2 gene and alcohol dependence (AD), drug dependence (DD), and affective disorders, using a novel extended case-control structured association method. Six markers at CHRM2 and 38 ancestry-informative markers were genotyped in a sample of 871 subjects, including 333 healthy controls and 538 AD and/or DD subjects (415 with AD and 346 with DD). The same CHRM2 markers were genotyped in a sample of 137 subjects with affective disorders. All 6 markers were in Hardy-Weinberg equilibrium in controls, but rs1824024 was in Hardy-Weinberg disequilibrium in the AD and DD groups. Regression analysis identified specific alleles, genotypes, haplotypes, and diplotypes that were significantly associated with risk for each disorder. Luo et al. (2005) concluded that variation in the CHRM2 gene may predispose to alcohol dependence, drug dependence, and affective disorders.

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 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 12q24

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.'

Among 1,032 Korean individuals, Kim et al. (2008) found that the combination of the ADH1B his48 allele (103720.0001) and the ALDH2 lys504 allele (100650.0001) offered protection against alcoholism. Individuals who carried both susceptibility alleles (arg48 and glu504, respectively) had a significantly increased risk for alcoholism (OR, 91.43; p = 1.4 x 10(-32)). Individuals with 1 protective and 1 susceptibility allele had a lesser increased risk for alcoholism (OR, 11.40; p = 3.5 x 10(-15)) compared to those with both protective alleles. Kim et al. (2008) calculated that alcoholism in the Korean population is 86.5% attributable to the detrimental effect of the ADH1B arg48 and/or the ALDH2 glu504 alleles.

Association with the NRXN3 Gene on Chromosome 14q

In a genotype study of 144 European Americans with alcohol dependence and 188 controls, Hishimoto et al. (2007) found an association between alcohol dependence and the T allele of rs8019381, located 23 bp from the NRXN3 (600567) exon 23 donor site (p = 0.0007; odds ratio = 2.46). The p value remained significant after correction for multiple testing (p = 0.0062). In postmortem human cerebral cortical tissue, 2 of the splice variants that encode transmembrane NRXN3 isoforms were expressed at significantly lower levels in individuals with the addiction-associated T allele of rs8019381 than in CC homozygotes. The data suggested that NRXN3 haplotypes that alter expression of specific NRXN3 isoforms may play a role in genetic vulnerabilities to alcohol dependence.

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%.

Association with Opioid Receptor Genes

Zhang et al. (2008) genotyped 11 SNPs in the OPRD1 gene (165195) in 1,063 European Americans, including 620 with substance dependence, 557 with alcohol dependence, 225 with cocaine dependence, 111 with opioid dependence (610064), and 443 controls. Although individual SNPs in general did not show significant associations after multiple corrections, haplotype analysis showed that a 6-SNP haplotype, which harbors the G allele of 80G-T (rs1042114) and the C allele of 921C-T (rs2234918), was significantly associated with alcohol dependence (p = 0.002) and opioid dependence (p less than 0.001). This haplotype yielded odds ratios of 6.43 for alcohol dependence and 50.57 for opioid dependence.

In a study of 327 primarily European American individuals with alcohol dependence and 358 controls, Zhang et al. (2008) found that a specific haplotype defined by 7 SNPs in the OPRK1 gene (165196) was significantly more common in those with alcohol dependence compared to controls (25.4% versus 18.6%, p = 0.004). However, there was no significant differences in allele, genotype, or global haplotype frequency distributions between cases and controls.

Edenberg et al. (2008) identified an 841-bp insertion/11-bp deletion (indel) polymorphism in the 5-prime untranslated region of the OPRK1 gene that was characterized by a net addition of 830 bp located 1986 bp upstream of the translation start site. Transient transfection studies showed that this upstream region was a promoter and that the presence of the indel polymorphism reduced transcriptional activity by about 50%. Genotyping studies of 1,914 individuals from 219 multiplex alcohol-dependent families of European American descent showed a significant association between presence of the indel polymorphism and increased risk for alcoholism (p = 0.01).

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.

In a rat operant ethanol self-administration model, Carnicella et al. (2008) found that GDNF (600837) infusion resulted in rapid and dose-dependent reduction in ethanol, but not sucrose, self-administration. A GDNF-mediated decrease in ethanol consumption (see 103780) was also observed in rats with a history of high voluntary ethanol intake. The action of GDNF on ethanol consumption was specific to the ventral tegmental area (VTA), since infusion into the substantia nigra did not affect responses to ethanol. GDNF administration activated the MAPK (176948) signaling pathway in the VTA, and inhibition of the MAPK pathway in the VTA blocked reduction of ethanol self-administration by GDNF. Carnicella et al. (2008) suggested that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.