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 ... 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 (dbSNP 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; dbSNP rs1154461, dbSNP rs1154468, dbSNP rs1154470, and dbSNP 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 dbSNP 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 dbSNP rs1229984, an independent association was observed between dbSNP rs1042026 in the ADH1B gene and alcohol intake and suggestive associations between alcohol consumption phenotypes and dbSNP rs1693482 in the ADH1C gene (see 103730.0001), dbSNP rs1230165 (ADH5; 103710) and dbSNP 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. - 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 (dbSNP rs427983, dbSNP rs419558, dbSNP 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 Artican 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 (dbSNP rs1824024, dbSNP rs2061174, and dbSNP 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 dbSNP 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 dbSNP 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 dbSNP 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 (dbSNP rs1042114) and the C allele of 921C-T (dbSNP 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).