1. 알코올 의존 유전 연구의 현재와 전망
한림대학교 한강성심병원
최인근

2. Alcoholism is highly familial
Alcohol preference can be selectively bred for in experimental animals
Concordance rate in monozygotic twins is 55%, 28% in dizygotic twins
Alcoholism rate is more like that of biologic father > foster father
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.
Alcohol Dependence, in Online Mendelian Inheritance in Man, 2007

3. Mapping 4q22-4q32 Prescott et al. Molec Psychiat 2006;11:603-611
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 = at D4S1611).
Prescott et al. Molec Psychiat 2006;11:

4. ADH Gene Cluster on 4q22 The genetic characteristics of alcohol
Association with the ADH Gene Cluster on Chromosome 4q22
Chai et al. (2005) examined polymorphisms in the ADH2 and ADH3 genes on chromosome 4q22 and in the ALDH2 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 and ADH3*2 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 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.
The genetic characteristics of alcohol
metabolism in type 1 alcoholism fall between
nonalcoholism and type 2 alcoholism.
Chai et al. Am J Psychiatry 2005;162:

5. ALDH2 Gene on Chromosome 12
The frequency of the ALDH2*1 allele was
significantly higher in men with alcohol
dependence than in healthy men.
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 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 allele was significantly higher in men with alcohol dependence than in healthy men. Also see 'Association with the ADH Gene Cluster on Chromosome 4q22.
Chai et al. Am J Psychiatry 2005;162:

6. GABA-A Receptor Gene Cluster on 5q34
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 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, including a pro385-to-ser substitution.
Radel et al. Arch Gen Psychiatry 2005;62:47-55

7. NPY Gene on Chromosome 7p15
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.
Neuropeptide Y (NPY) plays an important role in the
hypothalamic regulation of food intake and energy balance
Kauhanen et al. Am J Med Genet 2000;93:117–121

8. TAS2R16 Gene on 7q31
Association with the TAS2R16 Gene on Chromosome 7q31
Hinrichs et al. (2006) found a functional variant in a bitter-taste receptor (TAS2R16) 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.
The K172 allele of the K172N SNP showed an increased
risk of alcohol dependence, regardless of ethnicity.
Hinrich et al. Am J Hum Genet 2006; 78:103–111

9. CHRM2 Gene on 7q35 muscarinic acetylcholine receptor M2
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 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) (p = and 0.017). Haplotype analyses revealed that the most common haplotype, T-T-T (rs , rs , and rs324650), was undertransmitted to affected individuals with alcohol dependence and major depressive syndrome.
Wang et al. Hum Mol Genet 2004; 13:

10. COMT Gene on Chromosome 22q11
Type 1 (late-onset) alcoholics
markedly higher frequency of the low activity allele (L) of COMT gene
the population etiologic (attributable) fraction for the LL genotype in alcoholism was as high as 13.3%
Association with the COMT Gene on Chromosome 22q11
The enzyme catechol-O-methyltransferase (COMT), 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%.
Tiihonen et al. Molec Psychiat 1999;4:

11. DRD2 Gene on 11q23 The -141C deletion variant of DRD2
protective factor against the development of withdrawal symptoms
risk factor in paternal and grandpaternal alcoholism, suicide risk in alcoholics
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), 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.
Johann et al. Am J Med Genet 2005;132B:46-49

12. ANKK1 Gene (TaqIA Allele) on 11q23
Association with the ANKK1 Gene (TaqIA Allele) on Chromosome 11q23
In a study of the TaqIA polymorphism (see ANKK1) 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).
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
Hallikainen et al. Am J Med Genet 2003;119A:

13. Serotonin transporter
S allele of 5-HTTLPR
alcohol dependence
comorbid psychiatric conditions
early-onset alcohol dependence
more severe type of 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) 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 = ). 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 = ).
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.
Feinn et al. Am J Med Genet 2005;133B:79-84

14. What We Know There may be genes which are protective
The identification of protective and susceptibility genes may lead to the development of targeted prevention and intervention strategies that work
Genetic studies may help us understand the biological basis of alcohol dependence. For example, is individual variation rooted in the genetic basis for differences in ethanol metabolism (e.g., absorption and elimination rates)? Or, does it lie in differential central nervous system (CNS) effects of ethanol (e.g., neurotransmitter and receptor mechanisms)?
In fact, “protective” genes may exist, as well. Identification of susceptibility and protective genes may lead to the development of targeted prevention and intervention strategies.
Treatment works for those with a family history of alcoholism.

15. Pre-genomics era Classical genetics Modern genetics
1860 Mendel (genetic elements)
1911 Morgan (Drosophila)
Modern genetics
1953 DNA
2001 Human genome project 3x109 bp

16. Post-genomics era Epigenetics 1995 Epigenetics
1999 Human Epigenome Project
2004 Genome-wide DNA methylation

17. Epigenetics
The study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA

18. Epigenetics
Gene-regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next

19. Epigenetic control and gene silencing
function
expression
Misregulation of the epigenetic processes cause aberrant gene expressions. Therefore, defective epigenetic control often results in many human diseases, such as Rett Syndrom, imprinting disorders, aging, autoimmune diseases and cancer.

21. Qui Nature 2006

23. Fraga et al. PNAS 2005

24. Accumulation of epigenetic differences in identical twins
Fraga et al. PNAS 2005

26. Philibert et al. Am J Med Genet 2007;144B:101-105

28. Akbarian et al. Arch Gen Psychiat 2005;62:829-840

29. Akbarian et al. Arch Gen Psychiat 2005;62:829-840

30. Epigenetic Control of Alcoholism
DNA hypermethylation of the alpha synuclein promoter in alcoholism
HERP (homocysteine-induced endoplasmic reticulum protein) promoter DNA methylation increased in patients with alcohol dependence