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• W1984744289 abstract "During the past year, there has been a surge in genetic studies of alcohol and substance dependence. This increased interest is the result both of high repeated-heritability estimates of the addictive disorders and related phenotypes (typically ∼50%–60%) and of the appreciation that methods for detecting, mapping, and characterizing oligogenic susceptibility genes are rapidly improving. Thus, the full promise of genetics may become available to increase prevention and to improve the treatment of these extremely destructive common disorders. This article is primarily a review of recent human linkage and candidate-gene studies of alcoholism and related phenotypes, although we include other forms of substance dependence that show substantial comorbidity with alcoholism and with each other. We do not consider the large body of research that uses animal models to approach these questions. Several sets of diagnostic criteria for alcohol dependence have been used in genetic studies. Older diagnostic criteria (i.e., Diagnostic and Statistical Manual [DSM] IIIR [American Psychiatric Association American Psychiatric Association, 1987American Psychiatric Association Diagnostic and statistical manual of mental disorders. 3d ed., revision. APA Press, Washington, DC1987: 166-175Google Scholar] and Feighner [Feighner et al. Feighner et al., 1972Feighner JP Robins E Guze SB Woodruff Jr, RA Winokur G Munoz R Diagnostic criteria for use in psychiatric research.Arch Gen Psychiatry. 1972; 26: 57-63Crossref PubMed Scopus (3878) Google Scholar] criteria) prominently featured social and psychological problems as well as biomedical symptoms of dependence (i.e., tolerance, craving, loss of control, and withdrawal). Recently implemented criteria (DSM IV [American Psychiatric Association American Psychiatric Association, 1994American Psychiatric Association Diagnostic and statistical manual of mental disorders. 4th ed. APA Press, Washington, DC1994: 194-196Google Scholar and International Classification of Disease [ICD] 10 [World Health Organization World Health Organization, 1993World Health Organization International classification of disease. 10th ed. World Health Organization, Geneva1993: 56-59Google Scholar]) are more narrowly defined, require more symptoms for diagnosis, and feature biomedical symptoms of dependence. The criteria sets classify individuals in overlapping, nested, reliable categories that have been validated by their predictive value. The symptoms and criteria for a diagnosis of dependence are similar across substances, including nicotine. As part of the alcohol-dependence syndrome, tolerance of the intoxicating effects of alcohol usually occurs. Thus, increasing amounts are necessary to maintain the same effect. Debilitating withdrawal symptoms, including tremors and confusion, may occur when consumption ceases or is abruptly reduced, symptoms that are rapidly abolished if sufficient alcohol is consumed. Physical, psychological, and social impairment often is progressive or proceeds intermittently, resulting in trouble at work, deteriorating health, and destruction of family relationships. Symptoms tend to cluster at the onset, and rapid deterioration may follow an apparent period of social or controlled drinking. Alcohol dependence (alcoholism) is a common familial disorder that is a leading cause of morbidity and premature death (Caces et al. Caces et al., 1995Caces M Stinson FS Dufour MC Trends in alcohol-related morbidity among short-stay community hospital discharges, United States. Division of Biometry and Epidemiology, National Institute of Alcohol Abuse and Alcoholism, Rockville, MD1995Google Scholar). The heritability of risk for alcohol dependence has been estimated by studies of the adopted-away offspring of affected and unaffected parents (∼39% [Cloninger et al. Cloninger et al., 1981Cloninger CR Bohman M Sigvaardson S Inheritance of alcohol abuse: cross-fostering analysis of adopted men.Arch Gen Psychiatry. 1981; 38: 861-868Crossref PubMed Scopus (1343) Google Scholar]) and by twin studies (∼60% [Heath et al. Heath et al., 1997Heath AC Bucholz KK Madden PAF Dinwiddie SH Slutske WS Bierut LJ Stathan DJ et al.Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men.Psychol Med. 1997; 27: 1381-1396Crossref PubMed Scopus (682) Google Scholar]). Alcoholics in the community are at increased risk for affective and anxiety disorders, behavioral (externalizing) disorders of childhood, antisocial personality disorder, and drug dependence, including nicotine dependence (Kessler et al. Kessler et al., 1997Kessler RC Crum RM Warner LA Nelson CB Schulenberg J Anthony JC Lifetime co-occurrence of DSM IIIR alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey.Arch Gen Psychiatry. 1997; 54: 313-321Crossref PubMed Scopus (1591) Google Scholar). Nonalcoholic relatives in alcoholic families are also at increased risk. Family and twin studies that test the independence of alcohol dependence and its comorbid disorders support the existence of both common genetic liabilities and disease-specific genetic factors (Bierut et al. Bierut et al., 1998Bierut LJ Dinwiddie SH Begleiter H Crowe RR Hesselbrock V Nurnberger Jr, JI Porjesz B et al.Familial transmission of substance dependence: alcohol marijuana, cocaine, and habitual smoking.Arch Gen Psychiatry. 1998; 55: 982-988Crossref PubMed Scopus (370) Google Scholar; Tsuang et al. Tsuang et al., 1998Tsuang MT Lyons MJ Meyer JM Doyle T Eisen SA Goldberg J True W et al.Co-occurrence of abuse of different drugs in men.Arch Gen Psychiatry. 1998; 55: 967-972Crossref PubMed Scopus (536) Google Scholar). For example, the genetic correlations between alcoholism and affective disorders and alcoholism and nicotine dependence has been reported to be .50 and .68, respectively (Kendler et al. Kendler et al., 1998Kendler KS Heath AC Neale MC Kellser RC Eaves LJ Alcoholism and major depression in women: a twin study of the causes of comorbidity.Arch Gen Psychiatry. 1998; 50: 690-698Crossref Scopus (192) Google Scholar; True et al. True et al., 1999True WR Xian H Scherrer JF Madden PF Bucholz KK Heath AC Eisen SA Common genetic vulnerability for nicotine and alcohol dependence in men.Arch Gen Psychiatry. 1999; 56: 655-661Crossref PubMed Scopus (398) Google Scholar). Several heritable quantitative traits that may be closely related to the susceptibility to develop alcoholism, including electroencephalographic patterns and measures of personality, have also been measured in alcoholics and their families. Studies that use these features may be more successful in identifying susceptibility genes than those that rely on a diagnosis of overt alcoholism. Event-related brain potentials (ERPs) are voltage measures of electroencephalographic activity following visual or auditory stimuli. The P3 potential represents a positive deflection 300–500 ms after a stimulus and is elicited when a stimulus is perceived and attentional resources are allocated toward its processing. The amplitude of the P3 potential of abstinent, as well as active, alcoholics is reduced, suggesting that it may be a trait marker for the disorder. Begleiter (Begleiter et al., 1984Begleiter H Porjesz B Bihari B Kissin B Event-related potentials in boys at risk for alcoholism.Science. 1984; 225: 1493-1496Crossref PubMed Scopus (526) Google Scholar) reported, in a controlled study, that the amplitude of the P3 potential was significantly reduced in the preadolescent sons of alcoholic fathers, although the sons had never consumed alcohol or illicit drugs. Subsequent research has confirmed and extended these findings to the daughters of alcoholics. Furthermore, reduction of the P3 potential in abstinent alcoholics and in high-risk nonalcoholic offspring has been significantly related to the number of alcoholic relatives rather than to individual alcohol intake (Pfefferbaum et al. Pfefferbaum et al., 1991Pfefferbaum A Ford JM White PM Marathon D Event-related potentials in alcoholic men: P3 amplitude reflects family history but not alcohol consumption.Alcohol Clin Exp Res. 1991; 15: 839-850Crossref PubMed Scopus (164) Google Scholar). Almasy et al. (Almasy et al., 1999Almasy L Porjesz B Blangero J Chorlian DV O'Connor SJ Kuperman S Rohrbaugh J Heritability of event-related brain potentials in families with a history of alcoholism.Neuropsych Genet. 1999; 88: 383-390Crossref Scopus (67) Google Scholar) reported that the heritability of the P3 amplitude varied between .49 and .60. Taken together, these studies suggest that the amplitude of the P3 ERP is well suited to linkage and association studies for the detection of alcoholism-susceptibility genes. Cloninger (Cloninger et al., 1993Cloninger CR Svrakic DM Przybeck TR A psychobiological model of temperament and character.Arch Gen Psychiatry. 1993; 50: 975-990Crossref PubMed Scopus (3769) Google Scholar) developed a psychobiological model of personality structure after a classical adoption study of alcoholism in Sweden. In this formulation of personality traits, four stable, quantitative dimensions of personality (harm avoidance, novelty seeking, reward dependence, and persistence) are measured by means of the Tridimensional Personality Questionnaire (TPQ). According to twin studies, each of the four dimensions is moderately heritable (40%–60%) and is influenced by different sets of genes. Their utility in genetic studies of alcoholism is suggested by the observation that childhood personality traits predict alcohol abuse in young adults. Furthermore, alcoholics have been reported to score higher for “harm avoidance” and “novelty seeking” and lower in “reward dependence” than do nonalcoholics. The Collaborative Study of the Genetics of Alcoholism (COGA) is a multicenter study whose goal is the detection and characterization of genes that influence susceptibility to alcohol dependence and related phenotypes. COGA systematically ascertained ∼1,200 families to assess the familial distribution of alcohol dependence and related disorders. Informative, cooperative families were accepted for more-detailed genetic study if ⩾3 interviewed first-degree relatives, including the proband, were affected. Pedigrees were then extended into second- and third-degree branches, depending on the availability of affected relatives. Adult lifetime psychiatric status was assessed by direct interview of all family members, and a detailed family history was obtained. Personality traits were assessed with the TPQ. Standardized electroencephalographic and ERP studies were conducted in neurophysiology labs that had been carefully calibrated to minimize center effects. Blood was drawn for DNA preparation and lymphoblastoid cell lines were developed and cryopreserved. COGA was designed as a two-stage genetic study with an initial sample and a larger replication sample. To date, a complete-genome survey of the initial sample of 105 families (987 individuals) densely affected with alcohol dependence has been completed. A genomewide survey of the replication sample (152 families with 1,219 individuals) is in analysis (351 markers). Phenotypic data and DNA from the initial sample are to be made available to the scientific community, as of September 1999. For linkage analyses, diagnosis of alcohol dependence required affected individuals to meet DSM IIIR and Feighner (Feighner et al., 1972Feighner JP Robins E Guze SB Woodruff Jr, RA Winokur G Munoz R Diagnostic criteria for use in psychiatric research.Arch Gen Psychiatry. 1972; 26: 57-63Crossref PubMed Scopus (3878) Google Scholar) criteria (termed “COGA” criteria). In a random community sample of control families, the expected lifetime prevalence of this phenotype is ∼17.5% in males and 4% in females, with a risk ratio for sibs of 2.8–7.8, depending on the sexes of probands and of sibs. Age at onset averaged ∼22 years. The genomewide screen examined 291 markers at an average intermarker distance of 13.8 cM, using a set of 382 affected sibling pairs. Numerous studies have already used the data from COGA to probe linkage of specific alcoholism-related phenotypes (table 1). Evidence for linkage with susceptibility to developing alcohol dependence was reported (Reich et al. Reich et al., 1998Reich T Edenberg HJ Goate A Williams JT Rice JP Van Eerdewegh P Foroud T et al.Genome-wide search for genes affecting the risk for alcohol dependence.Am J Med Genet. 1998; 81: 207-215Crossref PubMed Scopus (616) Google Scholar; ASPEX 1999) on chromosomes 1, 2, and 7. The most significant finding was a LOD score of 3.5 on chromosome 7. On chromosome 1, two peaks separated by 60 cM were observed, with LOD scores of 2.9 and 1.6. When more-stringent diagnostic criteria were used (ICD 10 criteria), the linkage finding on chromosome 1 was still significant, and a region on chromosome 16 now gave evidence for linkage. Moreover, linkage analysis of an “unaffected but exposed” phenotype (individuals who drank but had few, if any, symptoms of alcohol dependence) suggested that a protective locus exists on chromosome 4 near the loci for alcohol dehydrogenases (ADH). “Protective” ADH alleles that reduce alcohol consumption have been found in Asian populations, so this finding in a largely African American and non-Hispanic white sample is intriguing.Table 1Evidence for Genetic Linkage from Genomewide Surveys for Alcohol Dependence And Related PhenotypesMethod of Analysis and PhenotypeMaximum LOD ScoreChromosome (Distance from pter [cM])Extended pedigree variance components (SOLAR) ERPs (P3 amplitude)aBegleiter et al. (1998). O2 leadbLeads on the scalp: O 2=right occipital, C z=median central, T 8=right temporal (American Electroencephalographic Society 1991).3.282 (218) Cz leadbLeads on the scalp: O 2=right occipital, C z=median central, T 8=right temporal (American Electroencephalographic Society 1991).3.416 (213)1.825 (73) T8 leadbLeads on the scalp: O 2=right occipital, C z=median central, T 8=right temporal (American Electroencephalographic Society 1991).2.105 (76)2.0713 (45) Harm avoidancecCloninger et al. (1998). Also referred to as anxiety proneness.3.2dThis locus also displayed evidence for epistatic interaction with other loci: chr18, 20 cM, joint two-locus LOD 4.5; chr20, 0 cM, joint two-locus LOD 4.6; chr21, 26 cM, joint two-locus LOD 5.1.8 (17)Multipoint affected sib pairs (SIBPHASE [ASPEX]) Alcohol dependence (COGA diagnosis)eReich et al. (1998). DSM III-R (American Psychiatric Association 1987) plus Feighner (Feighner et al. 1972) criteria.2.931 (169)3.497 (94)1.802 (92) “Unaffected” by alcohol dependencefReich et al. (1998).2.504 (87) Severe alcohol dependencegForoud et al. (1998). Defined by a multivariate latent class analysis of alcoholism symptoms.4.016 (14)Multipoint QTL (SIBPAL [SAGE]) Haseman-Elston regression Alcohol dependencehLong et al. (1998). Native American population.(DSM III-R)3.111 (0)2.84 (68)a Begleiter et al. (Begleiter et al., 1998Begleiter H Porjesz B Reich T Edenberg HJ Goate A Blangero J Almasy L et al.Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.Electroencephalogr Clin Neurophysiol. 1998; 108: 244-250Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar).b Leads on the scalp: O 2=right occipital, C z=median central, T 8=right temporal (American Electroencephalographic Society American Electroencephalographic Society, 1991American Electroencephalographic Society American Electroencephalographic Society guidelines for standard electrode position nomenclature.J Clin Neurophysiol. 1991; 8: 200-202Crossref PubMed Scopus (956) Google Scholar).c Cloninger et al. (Cloninger et al., 1998Cloninger CR Van Eerdewegh P Goate A Edenberg HJ Blangero J Hesselbrock V Reich T et al.Anxiety proneness linked to epistatic loci in genome scan of human personality traits.Am J Med Genet. 1998; 81: 313-317Crossref PubMed Scopus (135) Google Scholar). Also referred to as anxiety proneness.d This locus also displayed evidence for epistatic interaction with other loci: chr18, 20 cM, joint two-locus LOD 4.5; chr20, 0 cM, joint two-locus LOD 4.6; chr21, 26 cM, joint two-locus LOD 5.1.e Reich et al. (Reich et al., 1998Reich T Edenberg HJ Goate A Williams JT Rice JP Van Eerdewegh P Foroud T et al.Genome-wide search for genes affecting the risk for alcohol dependence.Am J Med Genet. 1998; 81: 207-215Crossref PubMed Scopus (616) Google Scholar). DSM III-R (American Psychiatric Association American Psychiatric Association, 1987American Psychiatric Association Diagnostic and statistical manual of mental disorders. 3d ed., revision. APA Press, Washington, DC1987: 166-175Google Scholar) plus Feighner (Feighner et al. Feighner et al., 1972Feighner JP Robins E Guze SB Woodruff Jr, RA Winokur G Munoz R Diagnostic criteria for use in psychiatric research.Arch Gen Psychiatry. 1972; 26: 57-63Crossref PubMed Scopus (3878) Google Scholar) criteria.f Reich et al. (Reich et al., 1998Reich T Edenberg HJ Goate A Williams JT Rice JP Van Eerdewegh P Foroud T et al.Genome-wide search for genes affecting the risk for alcohol dependence.Am J Med Genet. 1998; 81: 207-215Crossref PubMed Scopus (616) Google Scholar).g Foroud et al. (Foroud et al., 1998Foroud T Bucholz KK Edenberg HJ Goate A Neuman RJ Porjesz B Koller DL et al.Linkage of an alcoholism-related severity phenotype to chromosome 16.Alcohol Clin Exp Res. 1998; 22: 2035-2042Crossref PubMed Google Scholar). Defined by a multivariate latent class analysis of alcoholism symptoms.h Long et al. (Long et al., 1998Long JC Knowler WC Hanson RL Robin RW Urbanek M Moore E Bennett PH et al.Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population.Am J Med Genet. 1998; 81: 216-221Crossref PubMed Scopus (289) Google Scholar). Native American population. Open table in a new tab Long et al. (Long et al., 1998Long JC Knowler WC Hanson RL Robin RW Urbanek M Moore E Bennett PH et al.Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population.Am J Med Genet. 1998; 81: 216-221Crossref PubMed Scopus (289) Google Scholar) reported a genomewide scan for genetic linkage to alcohol dependence (DSM III-R criteria) in a Southwestern American Indian tribe. Clinical evaluations and genotypes were available for 152 subjects from extended pedigrees forming 172 sib pairs. Multipoint analysis of sib pairs provided highly suggestive evidence for linkage on chromosomes 4 and 11 (LOD scores of 2.8 and 3.1, respectively). Both regions harbored neurogenetic candidate genes. The region on chromosome 4 is near the gene for the β1 GABA receptor, and the region on chromosome 11 is near genes for tyrosine hydroxylase and dopamine D4 receptor. The region on chromosome 4 that contains the ADH loci was also implicated in this study, supporting the findings from the COGA dataset. Foroud et al. (Foroud et al., 1998Foroud T Bucholz KK Edenberg HJ Goate A Neuman RJ Porjesz B Koller DL et al.Linkage of an alcoholism-related severity phenotype to chromosome 16.Alcohol Clin Exp Res. 1998; 22: 2035-2042Crossref PubMed Google Scholar) used latent class analysis, a statistical method for finding subtypes of related cases from multivariate categorical data, to derive a narrow phenotype of severe dependence. These authors built on the symptoms of alcohol dependence and nondiagnostic severity items in COGA, and their goal was to increase the power of linkage analysis by reducing genetic heterogeneity. Multipoint affected sib-pair linkage analysis with the derived phenotype yielded a LOD score of ∼4 on chromosome 16, in the same region where linkage had been suggested according to the ICD 10 criteria for alcohol dependence. Begleiter et al. (Begleiter et al., 1998Begleiter H Porjesz B Reich T Edenberg HJ Goate A Blangero J Almasy L et al.Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.Electroencephalogr Clin Neurophysiol. 1998; 108: 244-250Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) reported heritability estimates and genetic correlations for visual P3-amplitude ERPs recorded at 19 electrodes (grouped in 5 clusters) across the scalp in the COGA study. Individual heritabilities ranged 0.30–0.50. The genetic correlations between electrode measurements within clusters suggested that 81% of the genetic variation in P3 amplitude is shared in common. Begleiter et al. (Begleiter et al., 1998Begleiter H Porjesz B Reich T Edenberg HJ Goate A Blangero J Almasy L et al.Quantitative trait loci analysis of human event-related brain potentials: P3 voltage.Electroencephalogr Clin Neurophysiol. 1998; 108: 244-250Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) used a variance-components multipoint approach to search the genome for QTLs that influence P3 amplitude, making use of 607 individuals from 103 families, including 758 sib pairs. They reported evidence for genetic linkage on chromosomes 2, 6, 5, and 13, with maximum LOD scores of 3.28, 3.41, 2.10, and 2.07, respectively. Even when the large number of tests of linkage are taken into account, empirical estimates show these results to be highly significant. Cloninger et al. (Cloninger et al., 1998Cloninger CR Van Eerdewegh P Goate A Edenberg HJ Blangero J Hesselbrock V Reich T et al.Anxiety proneness linked to epistatic loci in genome scan of human personality traits.Am J Med Genet. 1998; 81: 313-317Crossref PubMed Scopus (135) Google Scholar) carried out a genomewide scan of personality traits measured by the TPQ in 758 sib pairs from the COGA sample, using the program SOLAR (Blangero and Almasy Blangero and Almasy, 1996Blangero J Almasy L SOLAR: sequential oligogenic linkage analysis routines. Population Genetics Laboratory, Southwest Foundation for Biomedical Research, San Antonio, Texas1996Google Scholar) to test for quantitative trait loci. This work showed that harm avoidance, a measure of proneness to anxiety, was significantly linked to a locus on chromosome 8 that explained 38% of the variance in this trait. There was also significant evidence for epistatic interaction between this locus and others on chromosomes 18, 20, and 21. Taken together, these loci explained most of the heritable variance for this trait. These genomewide screens suggest that multiple genes of small effect increase or decrease susceptibility to developing alcohol dependence. However, of the loci implicated so far, only a region on chromosome 4 is supported by evidence from two independent studies. Furthermore, closely related traits appear to be linked to distinct genomic regions; even traits that are genetically correlated do not share evidence for linkage at common loci when the phenotypes are analyzed independently. The Genetic Analysis Workshop in September Almasy and Borecki, in pressAlmasy L, Borecki IG. Genetic Analysis Workshop 11: Exploring genetic analysis of complex traits through the paradigm of alcohol dependence: summary of GAW11 contributions. Genet Epidemiol (in press)Google Scholar (GAW 11) featured phenotypic and genotypic data from COGA (Almasy and Borecki, in press). Investigators analyzed clinical diagnoses, detailed symptom profiles, platelet monoamine oxidase (see Shih and Thompson Shih and Thompson, 1999Shih JC Thompson RF Monoamine oxidase in neuropsychiatry and behavior.Am J Hum Genet. 1999; 65 (in this issue): 593-598Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar [in this issue]) activity measures, personality trait measures (TPQ), multiple ERP measures of visual P3 amplitude, and tobacco consumption in 987 individuals (from 105 kindreds). Genotypes from a genomewide screen were also provided. Workshop proceedings include 68 papers with many new approaches to quantitative and qualitative linkage and linkage/disequilibrium. Of particular interest was the emergence of linkage and disequilibrium analyses of multiple loci using measures from several domains. Analyses at multiple loci may lead to detection of epistatic interactions, revealing much larger genetic effects than do individual analyses of oligogenic loci. A note of caution is in order, however. Although some robust findings were reported—for example, the evidence of a susceptibility locus on chromosome 1—results from both qualitative and quantitative traits were sensitive to changes in phenotype definition. Candidate-gene studies of alcohol dependence are reported regularly. The dopamine receptor gene DRD2, which maps to chromosome 11 in humans, has received much attention, as the dopamine system has been correlated with novelty seeking and the CNS reward mechanism (Edenberg et al. Edenberg et al., 1998aEdenberg HJ Foroud T Koller DL Goate A Rice J Van Eerdewegh P Reich T et al.A family-based analysis of the association of the dopamine D2 receptor (DRD2) with alcoholism.Alcohol Clin Exp Res. 1998; 22: 505-512Crossref PubMed Scopus (99) Google Scholara). A case-control study reported that a TaqI-A1 polymorphism in this gene is associated with alcoholism (especially with “severe” alcoholism; Blum et al. Blum et al., 1990Blum K Noble EP Sheridan PJ Montgomery A Ritchie T Jagadeeswaran P Nogami H et al.Allelic association of human dopamine D2 receptor gene in alcoholism.JAMA. 1990; 263: 2055-2060Crossref PubMed Scopus (773) Google Scholar); since then, many studies have disputed this result. However, this sequence variant is not a functional polymorphism and is >10 kb from the coding region of the DRD2 gene, which makes a tight association unlikely. Many studies have shown that the frequency of the A1 allele is not increased in alcoholic populations. In particular, a study of several different ethnic groups reported that the frequency of the TaqI A1 allele varied from .18–.20 in whites to .80 in Cheyennes, suggesting that the earlier finding may have been spurious population association (Goldman et al. Goldman et al., 1993Goldman D Brown GL Albaugh B Robin R Goodson S Trunzo M Akhtar L et al.DRD2 dopamine receptor genotype linkage disequilibrium, and alcoholism in American Indians and other populations.Alcohol Clin Exp Res. 1993; 17: 199-204Crossref PubMed Scopus (85) Google Scholar). An analysis of the COGA data set was undertaken with the transmission/disequilibrium test (TDT) and the affected-family–based association test (AFBAC) to avoid false positives caused by population stratification. This study found no evidence of linkage or association between the DRD2locus and alcohol dependence (Edenberg et al. Edenberg et al., 1998aEdenberg HJ Foroud T Koller DL Goate A Rice J Van Eerdewegh P Reich T et al.A family-based analysis of the association of the dopamine D2 receptor (DRD2) with alcoholism.Alcohol Clin Exp Res. 1998; 22: 505-512Crossref PubMed Scopus (99) Google Scholara). ADH and aldehyde dehydrogenases (ALDH) have been well studied as protective factors. These enzymes are responsible for the oxidative metabolism of ethanol. Functional polymorphisms of the ADH2, ADH3, and ALDH2 genes have received particular scrutiny. The mutant allele ALDH2*2 acts dominantly over the normal ALDH2*1 allele and eliminates detectable ALDH2 activity in the liver, causing facial flushing, light-headedness, palpitations, and nausea when alcohol is consumed (Thomasson et al. Thomasson et al., 1991Thomasson HR Edenberg HJ Crabb DW Mai X-L Jerome RE Li T-K Wag S-P et al.Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.Am J Hum Genet. 1991; 48: 677-681PubMed Google Scholar). A role for ALDH2 in the development of alcoholism has been firmly established in several Asian populations. In particular, multiple studies of Chinese (especially the Han subpopulation), Japanese, and Korean populations show increased frequency of ALDH2*1homozygotes in alcoholics over controls. It thus appears that the ALDH2*2allele protects individuals from the development of alcoholism. However, this allele is rare in non-Asians (Neumark et al. Neumark et al., 1998Neumark YD Friedlander Y Thomasson HR Li T-K Association of the ADH2*2 allele with reduced ethanol consumption in Jewish men in Israel: a pilot study.J Stud Alcohol. 1998; 59: 133-139PubMed Google Scholar). Recently, several studies of ADH in Asian and non-Asian populations have been reported. A study of ADH and ALDH in Chinese men showed that the frequency of ALDH2*2 was significantly lower in alcoholics than in controls (Thomasson et al. Thomasson et al., 1991Thomasson HR Edenberg HJ Crabb DW Mai X-L Jerome RE Li T-K Wag S-P et al.Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.Am J Hum Genet. 1991; 48: 677-681PubMed Google Scholar). The ADH2*2 and ADH3*1 alleles (which are associated with high rates of acetaldehyde production) were shown to have significantly lower frequency in alcoholics than in controls, even after subpopulations homozygous for ALDH2*1 were extracted. A study of 377 male and female subjects of European descent found that the ADH2 genotype influences alcohol dependence, consumption, and problems in men, although no influence was seen in women of the same background (Whitfield et al. Whitfield et al., 1998Whitfield JB Nightingale BN Bucholz KK Madden PAF Heath AC Martin NG ADH Genotypes and Alcohol Use and Dependence in Europeans.Alcohol Clin Exp Res. 1998; 22: 1463-1469Crossref PubMed Scopus (124) Google Scholar). Another study compared treatment-enrolled heroin-dependent Jewish men in Israel to a Jewish control group living in the same city. All individuals studied were homozygous for the ALDH2*1allele. Neumark et al. (Neumark et al., 1998Neumark YD Friedlander Y Thomasson HR Li T-K Association of the ADH2*2 allele w" @default.
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• W1984744289 title "Genetic Studies of Alcoholism and Substance Dependence" @default.
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