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Strong Association of the Alcohol Dehydrogenase 1B Gene (ADH1B) with Alcohol Dependence and Alcohol-Induced Medical Diseases

  • Dawei Li
    Correspondence
    Address correspondence to Dawei Li, Ph.D., Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06511; or 300 George Street, Suite 503, New Haven, CT 06511
    Affiliations
    Department of Psychiatry, School of Medicine, Yale University, New Haven, and VA Connecticut Healthcare Center, West Haven, CT
    Search for articles by this author
  • Hongyu Zhao
    Affiliations
    Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, and VA Connecticut Healthcare Center, West Haven, CT

    Department of Genetics, School of Medicine, Yale University, New Haven, and VA Connecticut Healthcare Center, West Haven, Connecticut
    Search for articles by this author
  • Joel Gelernter
    Affiliations
    Department of Psychiatry, School of Medicine, Yale University, New Haven, and VA Connecticut Healthcare Center, West Haven, CT

    Department of Genetics, School of Medicine, Yale University, New Haven, and VA Connecticut Healthcare Center, West Haven, Connecticut
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      Background

      The alcohol dehydrogenase 1B gene (ADH1B) is hypothesized to affect predisposition to alcohol dependence (AD) and abuse. A variant of the ADH1B gene (rs1229984 or Arg48His; previously referred to as Arg [*1] and His [*1]) has been reported to be associated with reduced rates of alcohol and drug dependence. Different studies have produced inconclusive results regarding association between rs1229984 (or rs2066702) and substance dependence.

      Methods

      Using the cumulative association study literature from the past 21 years from both English- and Chinese-language publications, this meta-analysis seeks to clarify the contradictory findings and to examine whether the aggregate data provide new evidence of significant association.

      Results

      The results, based on a large sample size (9638 cases and 9517 controls), suggested strong associations with alcohol dependence and abuse as well as alcohol-induced liver diseases, with an allelic (Arg vs. His) p value being 1 × 10−36 and odds ratio (OR) (95% confidence intervals [CI]) 2.06 (1.84–2.31) under the random effects model. The dominant and recessive models produced larger ORs of 2.17 and 3.05, respectively. When more stringent criteria and subgroup analyses were imposed, the associations remained consistent and were strongest in various Asian groups (allelic p = 7 × 10−42 and OR (95% CI) = 2.24 [1.99–2.51] with ORs of 2.16 and 4.11 for dominant and recessive models, respectively).

      Conclusions

      Our findings provide further strong evidence for the involvement of the ADH1B gene in the pathogenesis of alcohol dependence and abuse as well as for some alcohol-induced medical diseases in the multiple ethnic populations—in particular, certain Asian populations.

      Key Words

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      References

        • Grant B.F.
        • Dufour M.C.
        • Harford T.C.
        Epidemiology of alcoholic liver disease.
        Semin Liver Dis. 1988; 8: 12-25
        • Dreiling D.A.
        • Koller M.
        The natural history of alcoholic pancreatitis: Update 1985.
        Mt Sinai J Med. 1985; 52: 340-342
        • Zintzaras E.
        • Stefanidis I.
        • Santos M.
        • Vidal F.
        Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?.
        Hepatology. 2006; 43: 352-361
        • Yoshida A.
        • Hsu L.C.
        • Yasunami M.
        Genetics of human alcohol-metabolizing enzymes.
        Prog Nucleic Acid Res Mol Biol. 1991; 40: 255-287
        • Osier M.
        • Pakstis A.J.
        • Kidd J.R.
        • Lee J.F.
        • Yin S.J.
        • Ko H.C.
        • et al.
        Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism.
        Am J Hum Genet. 1999; 64: 1147-1157
        • Luczak S.E.
        • Glatt S.J.
        • Wall T.L.
        Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians.
        Psychol Bull. 2006; 132: 607-621
        • Whitfield J.B.
        Alcohol dehydrogenase and alcohol dependence: Variation in genotype-associated risk between populations.
        Am J Hum Genet. 2002; 71 (author reply: 1250–1241): 1247-1250
        • Li D.
        • Collier D.A.
        • He L.
        Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia.
        Hum Mol Genet. 2006; 15: 1995-2002
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Duval S.
        • Tweedie R.
        Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Woolf B.
        On estimating the relation between blood group and disease.
        Ann Hum Genet. 1955; 19: 251-253
        • Higuchi S.
        • Matsushita S.
        • Murayama M.
        • Takagi S.
        • Hayashida M.
        Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism.
        Am J Psychiatry. 1995; 152: 1219-1221
        • Higuchi S.
        • Muramatsu T.
        • Matsushita S.
        • Murayama M.
        • Hayashida M.
        Polymorphisms of ethanol-oxidizing enzymes in alcoholics with inactive ALDH2.
        Hum Genet. 1996; 97: 431-434
        • Wei F.
        • Fan J.
        • Shen Y.
        • Tian C.
        • Zhou R.
        • Zheng X.
        • et al.
        A control study on the polymorphism of the ADH and ALDH genes in high risk alcoholic families of Han ethnic population.
        Chin J Psychiatry. 1999; 32: 164-166
        • Macgregor S.
        • Lind P.A.
        • Bucholz K.K.
        • Hansell N.K.
        • Madden P.A.
        • Richter M.M.
        • et al.
        Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: An integrated analysis.
        Hum Mol Genet. 2009; 18: 580-593
        • Khan A.J.
        • Husain Q.
        • Choudhuri G.
        • Parmar D.
        Association of polymorphism in alcohol dehydrogenase and interaction with other genetic risk factors with alcoholic liver cirrhosis.
        Drug Alcohol Depend. 2010; 109: 190-197
        • Tsuchihashi-Makaya M.
        • Serizawa M.
        • Yanai K.
        • Katsuya T.
        • Takeuchi F.
        • Fujioka A.
        • et al.
        Gene-environmental interaction regarding alcohol-metabolizing enzymes in the Japanese general population.
        Hypertens Res. 2009; 32: 207-213
        • Shimosegawa T.
        • Kume K.
        • Masamune A.
        SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan.
        J Gastroenterol Hepatol. 2008; 23: S82-S86
        • Kuo P.H.
        • Kalsi G.
        • Prescott C.A.
        • Hodgkinson C.A.
        • Goldman D.
        • van den Oord E.J.
        • et al.
        Association of ADH and ALDH genes with alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample.
        Alcohol Clin Exp Res. 2008; 32: 785-795
        • Choi I.G.
        • Kee B.S.
        • Son H.G.
        • Ham B.J.
        • Yang B.H.
        • Kim S.H.
        • et al.
        Genetic polymorphisms of alcohol and aldehyde dehydrogenase, dopamine and serotonin transporters in familial and non-familial alcoholism.
        Eur Neuropsychopharmacol. 2006; 16: 123-128
        • Sherman D.I.
        • Ward R.J.
        • Warren-Perry M.
        • Williams R.
        • Peters T.J.
        Association of restriction fragment length polymorphism in alcohol dehydrogenase 2 gene with alcohol induced liver damage.
        BMJ. 1993; 307: 1388-1390
        • Segado Soriano A.
        • Santiago Dorrego C.
        • Banares Canizares R.
        • Alvarez Fernandez E.
        • Bandres Moya F.
        • Gomez-Gallego F.
        • et al.
        Genetic susceptibility to the development of acute alcoholic hepatitis: Role of genetic mutations in dehydrogenase alcohol, aldehyde dehydrogenase and cytochrome P450 2E1.
        Rev Clín Esp. 2005; 205: 528-532
        • Hendershot C.S.
        • Collins S.E.
        • George W.H.
        • Wall T.L.
        • McCarthy D.M.
        • Liang T.
        • et al.
        Associations of ALDH2 and ADH1B genotypes with alcohol-related phenotypes in Asian young adults.
        Alcohol Clin Exp Res. 2009; 33: 839-847
        • Vaswani M.
        • Prasad P.
        • Kapur S.
        Association of ADH1B and ALDH2 gene polymorphisms with alcohol dependence: A pilot study from India.
        Hum Genomics. 2009; 3: 213-220
        • Shafe S.
        • Gilder D.A.
        • Montane-Jaime L.K.
        • Joseph R.
        • Moore S.
        • Crooks H.
        • et al.
        Co-morbidity of alcohol dependence and select affective and anxiety disorders among individuals of East Indian and African Ancestry in Trinidad and Tobago.
        West Indian Med J. 2009; 58: 164-172
        • Thomasson H.R.
        • Edenberg H.J.
        • Crabb D.W.
        • Mai X.L.
        • Jerome R.E.
        • Li T.K.
        • et al.
        Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.
        Am J Hum Genet. 1991; 48: 677-681
        • Chao Y.C.
        • Liou S.R.
        • Chung Y.Y.
        • Tang H.S.
        • Hsu C.T.
        • Li T.K.
        • et al.
        Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients.
        Hepatology. 1994; 19: 360-366
        • Thomasson H.R.
        • Crabb D.W.
        • Edenberg H.J.
        • Li T.K.
        • Hwu H.G.
        • Chen C.C.
        • et al.
        Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders.
        Alcohol Clin Exp Res. 1994; 18: 640-643
        • Maezawa Y.
        • Yamauchi M.
        • Toda G.
        • Suzuki H.
        • Sakurai S.
        Alcohol-metabolizing enzyme polymorphisms and alcoholism in Japan.
        Alcohol Clin Exp Res. 1995; 19: 951-954
        • Muramatsu T.
        • Wang Z.C.
        • Fang Y.R.
        • Hu K.B.
        • Yan H.
        • Yamada K.
        • et al.
        Alcohol and aldehyde dehydrogenase genotypes and drinking behavior of Chinese living in Shanghai.
        Hum Genet. 1995; 96: 151-154
        • Yamauchi M.
        • Maezawa Y.
        • Toda G.
        • Suzuki H.
        • Sakurai S.
        Association of a restriction fragment length polymorphism in the alcohol dehydrogenase 2 gene with Japanese alcoholic liver cirrhosis.
        J Hepatol. 1995; 23: 519-523
        • Chen W.J.
        • Loh E.W.
        • Hsu Y.P.
        • Chen C.C.
        • Yu J.M.
        • Cheng A.T.
        • et al.
        Alcohol-metabolising genes and alcoholism among Taiwanese Han men: Independent effect of ADH2, ADH3 and ALDH2.
        Br J Psychiatry. 1996; 168: 762-767
        • Nakamura K.
        • Iwahashi K.
        • Matsuo Y.
        • Miyatake R.
        • Ichikawa Y.
        • Suwaki H.
        • et al.
        Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2* 2.
        Alcohol Clin Exp Res. 1996; 20: 52-55
        • Tanaka F.
        • Shiratori Y.
        • Yokosuka O.
        • Imazeki F.
        • Tsukada Y.
        • Omata M.
        • et al.
        High incidence of ADH2*1/ALDH2*1 genes among Japanese alcohol dependents and patients with alcoholic liver disease.
        Hepatology. 1996; 23: 234-239
        • Chao Y.C.
        • Young T.H.
        • Tang H.S.
        • Hsu C.T.
        Alcoholism and alcoholic organ damage and genetic polymorphisms of alcohol metabolizing enzymes in Chinese patients.
        Hepatology. 1997; 25: 112-117
        • Chen W.J.
        • Loh E.W.
        • Hsu Y.P.
        • Cheng A.T.
        Alcohol dehydrogenase and aldehyde dehydrogenase genotypes and alcoholism among Taiwanese aborigines.
        Biol Psychiatry. 1997; 41: 703-709
        • Shen Y.C.
        • Fan J.H.
        • Edenberg H.J.
        • Li T.K.
        • Cui Y.H.
        • Wang Y.F.
        • et al.
        Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism.
        Alcohol Clin Exp Res. 1997; 21: 1272-1277
        • Shen Y.
        • Fan J.
        • Cui Y.
        • Zhou R.
        • Wang Y.
        • Tian C.
        • et al.
        A study of the correlation between alcohol dependence and polymorphism of alcohol-dehydrogenase genes and aldehyde-dehydrogenase genes among Mongolian and Han ethnic groups in China.
        Chin J Psychiatry. 1997; 30: 3-6
        • Fan J.
        • Shen Y.
        • Cui Y.
        • Tian C.
        • Zhou R.
        • Zhou C.
        • et al.
        ADH and ALDH genes among Korea and Elunchun ethnic groups in China.
        Chin J Psychiatry. 1998; 31: 209-212
        • Chen C.C.
        • Lu R.B.
        • Chen Y.C.
        • Wang M.F.
        • Chang Y.C.
        • Li T.K.
        • et al.
        Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism.
        Am J Hum Genet. 1999; 65: 795-807
        • Lee J.F.
        • Lu R.B.
        • Ko H.C.
        • Chang F.M.
        • Yin S.J.
        • Pakstis A.J.
        • et al.
        No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population.
        Alcohol Clin Exp Res. 1999; 23: 592-599
        • Amadeo S.
        • Noble E.P.
        • Fourcade-Amadeo M.L.
        • Tetaria C.
        • Brugiroux M.F.
        • Nicolas L.
        • et al.
        Association of D2 dopamine receptor and alcohol dehydrogenase 2 genes with Polynesian alcoholics.
        Eur Psychiatry. 2000; 15: 97-102
        • Chao Y.C.
        • Wang L.S.
        • Hsieh T.Y.
        • Chu C.W.
        • Chang F.Y.
        • Chu H.C.
        • et al.
        Chinese alcoholic patients with esophageal cancer are genetically different from alcoholics with acute pancreatitis and liver cirrhosis.
        Am J Gastroenterol. 2000; 95: 2958-2964
        • Paik Y.K.
        • Choi Y.
        • Lee C.G.
        • Kim I.K.
        Differences in Genetic Variation of ADH2 and ALDH2 between Alcoholics and Healthy Persons in Korea.
        Korean J Genet. 2000; 22: 117-126
        • Lee H.C.
        • Lee H.S.
        • Jung S.H.
        • Yi S.Y.
        • Jung H.K.
        • Yoon J.H.
        • et al.
        Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population.
        J Korean Med Sci. 2001; 16: 745-750
        • Park K.S.
        • Mok J.W.
        • Chung T.H.
        Genetic aspects and relative risk factors in alcoholism among Koreans.
        Korean J Genet. 2001; 23: 143-150
        • Xu K.
        • Liu X.H.
        • Nagarajan S.
        • Gu X.Y.
        • Goldman D.
        Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample.
        Am J Med Genet. 2002; 110: 45-50
        • Yu C.
        • Li Y.
        • Chen W.
        • Yue M.
        Genotype of ethanol metabolizing enzyme genes by oligonucleotide microarray in alcoholic liver disease in Chinese people.
        Chin Med J (Engl). 2002; 115: 1085-1087
        • Chao Y.C.
        • Wang S.J.
        • Chu H.C.
        • Chang W.K.
        • Hsieh T.Y.
        Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver.
        Alcohol Alcohol. 2003; 38: 431-436
        • Huang S.Y.
        • Lin W.W.
        • Ko H.C.
        • Lee J.F.
        • Wang T.J.
        • Chou Y.H.
        • et al.
        Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence.
        Alcohol Clin Exp Res. 2004; 28: 374-384
        • Kim S.A.
        • Kim J.W.
        • Song J.Y.
        • Park S.
        • Lee H.J.
        • Chung J.H.
        • et al.
        Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.
        Alcohol. 2004; 34: 115-120
        • Chai Y.G.
        • Oh D.Y.
        • Chung E.K.
        • Kim G.S.
        • Kim L.
        • Lee Y.S.
        • et al.
        Alcohol and aldehyde dehydrogenase polymorphisms in men with type I and type II alcoholism.
        Am J Psychiatry. 2005; 162: 1003-1005
        • Choi I.G.
        • Son H.G.
        • Yang B.H.
        • Kim S.H.
        • Lee J.S.
        • Chai Y.G.
        • et al.
        Scanning of genetic effects of alcohol metabolism gene (ADH1B and ADH1C) polymorphisms on the risk of alcoholism.
        Hum Mutat. 2005; 26: 224-234
        • Kim D.J.
        • Park B.L.
        • Yoon S.
        • Lee H.K.
        • Joe K.H.
        • Cheon Y.H.
        • et al.
        5′ UTR polymorphism of dopamine receptor D1 (DRD1) associated with severity and temperament of alcoholism.
        Biochem Biophys Res Commun. 2007; 357: 1135-1141
        • Kim D.J.
        • Choi I.G.
        • Park B.L.
        • Lee B.C.
        • Ham B.J.
        • Yoon S.
        • et al.
        Major genetic components underlying alcoholism in Korean population.
        Hum Mol Genet. 2008; 17: 854-858
        • Maruyama K.
        • Harada S.
        • Yokoyama A.
        • Naruse S.
        • Hirota M.
        • Nishimori I.
        • et al.
        Association analysis among polymorphisms of the various genes and chronic alcoholic pancreatitis.
        J Gastroenterol Hepatol. 2008; 23: S69-S72
        • He G.
        • Zhong S.
        • Gao L.
        • Bao J.
        • Gao C.
        • Wu W.
        • et al.
        Research on the relationship between ADH2, CYP2E1 gene polymorphism and alcohol dependence syndrome.
        J Med Res. 2009; 38: 67-70
        • Jing Q.
        • Zhong S.
        • Gao L.
        • Wang X.
        • Dou S.
        • He G.
        • et al.
        Association analyses of ADH2, ALDH2, and CYP4502E1 genetic polymorphisms with alcohol dependence syndrome in Yunnan Han population.
        Chin J Drugs Depend. 2009; 18: 341-370
        • Guo W.
        • Wang Q.
        • Lanzi G.
        • Luobu O.
        • Ma X.
        • Wang Y.
        • et al.
        Interaction among genes influencing ethanol metabolism and sex is association with alcohol use disorders in a Tibet population.
        Am J Med Genet B Neuropsychiatr Genet. 2010; 153B: 561-569
        • Tan E.C.
        • Lim L.
        • Leong J.Y.
        • Lim J.Y.
        • Lee A.
        • Yang J.
        • et al.
        Alcohol and aldehyde dehydrogenase polymorphisms in Chinese and Indian populations.
        Subst Use Misuse. 2010; 45: 1-14
        • Couzigou P.
        • Fleury B.
        • Groppi A.
        • Cassaigne A.
        • Begueret J.
        • Iron A.
        Genotyping study of alcohol dehydrogenase class I polymorphism in French patients with alcoholic cirrhosis.
        Alcohol Alcohol. 1990; 25: 623-626
        • Day C.P.
        • Bashir R.
        • James O.F.
        • Bassendine M.F.
        • Crabb D.W.
        • Thomasson H.R.
        • et al.
        Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage.
        Hepatology. 1991; 14: 798-801
        • Gilder F.J.
        • Hodgkinson S.
        • Murray R.M.
        ADH and ALDH genotype profiles in Caucasians with alcohol-related problems and controls.
        Addiction. 1993; 88: 383-388
        • Vidal F.
        • Perez J.
        • Panisello J.
        • Toda R.
        • Gutierrez C.
        • Richart C.
        • et al.
        Atypical liver alcohol dehydrogenase in the Spanish population: Its relation with the development of alcoholic liver disease.
        Alcohol Clin Exp Res. 1993; 17: 782-785
        • Pares X.
        • Farres J.
        • Pares A.
        • Soler X.
        • Panes J.
        • Ferre J.L.
        • et al.
        Genetic polymorphism of liver alcohol dehydrogenase in Spanish subjects: Significance of alcohol consumption and liver disease.
        Alcohol Alcohol. 1994; 29: 701-705
        • Espinos C.
        • Sanchez F.
        • Ramirez C.
        • Juan F.
        • Najera C.
        Polymorphism of alcohol dehydrogenase genes in alcoholic and nonalcoholic individuals from Valencia (Spain).
        Hereditas. 1997; 126: 247-253
        • Neumark Y.D.
        • Friedlander Y.
        • Thomasson H.R.
        • 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: 133-139
        • Whitfield J.B.
        • Nightingale B.N.
        • Bucholz K.K.
        • Madden P.A.
        • Heath A.C.
        • Martin N.G.
        • et al.
        ADH genotypes and alcohol use and dependence in Europeans.
        Alcohol Clin Exp Res. 1998; 22: 1463-1469
        • Rodrigo L.
        • Alvarez V.
        • Rodriguez M.
        • Perez R.
        • Alvarez R.
        • Coto E.
        • et al.
        N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: A case-control study.
        Scand J Gastroenterol. 1999; 34: 303-307
        • Borras E.
        • Coutelle C.
        • Rosell A.
        • Fernandez-Muixi F.
        • Broch M.
        • Crosas B.
        • et al.
        Genetic polymorphism of alcohol dehydrogenase in Europeans: The ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1.
        Hepatology. 2000; 31: 984-989
        • Ogurtsov P.P.
        • Garmash I.V.
        • Miandina G.I.
        • Guschin A.E.
        • Itkes A.V.
        • Moiseev V.S.
        • et al.
        Alcohol dehydrogenase ADH2-1 and ADH2-2 allelic isoforms in the Russian population correlate with type of alcoholic disease.
        Addict Biol. 2001; 6: 377-383
        • Chambers G.K.
        • Marshall S.J.
        • Robinson G.M.
        • Maguire S.
        • Newton-Howes J.
        • Chong N.L.
        • et al.
        The genetics of alcoholism in Polynesians: Alcohol and aldehyde dehydrogenase genotypes in young men.
        Alcohol Clin Exp Res. 2002; 26: 949-955
        • Frenzer A.
        • Butler W.J.
        • Norton I.D.
        • Wilson J.S.
        • Apte M.V.
        • Pirola R.C.
        • et al.
        Polymorphism in alcohol-metabolizing enzymes, glutathione S-transferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis.
        J Gastroenterol Hepatol. 2002; 17: 177-182
        • Vidal F.
        • Lorenzo A.
        • Auguet T.
        • Olona M.
        • Broch M.
        • Gutierrez C.
        • et al.
        Genetic polymorphisms of ADH2, ADH3, CYP4502E1 Dra-I and Pst-I, and ALDH2 in Spanish men: Lack of association with alcoholism and alcoholic liver disease.
        J Hepatol. 2004; 41: 744-750
        • Luo X.
        • Kranzler H.R.
        • Zuo L.
        • Wang S.
        • Schork N.J.
        • Gelernter J.
        • et al.
        Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans.
        Hum Mol Genet. 2007; 16: 380-390
        • Cichoz-Lach H.
        • Celinski K.
        • Slomka M.
        Alcohol-Metabolizing Enzyme Gene Polymorphisms and Alcohol Chronic Pancreatitis Among Polish Individuals.
        in: HPB, Oxford2008: 138-143 (Vol 10.)
        • Sherva R.
        • Rice J.P.
        • Neuman R.J.
        • Rochberg N.
        • Saccone N.L.
        • Bierut L.J.
        • et al.
        Associations and interactions between SNPs in the alcohol metabolizing genes and alcoholism phenotypes in European Americans.
        Alcohol Clin Exp Res. 2009; 33: 848-857
        • Wall T.L.
        • Carr L.G.
        • Ehlers C.L.
        Protective association of genetic variation in alcohol dehydrogenase with alcohol dependence in Native American Mission Indians.
        Am J Psychiatry. 2003; 160: 41-46
        • Konishi T.
        • Calvillo M.
        • Leng A.S.
        • Feng J.
        • Lee T.
        • Lee H.
        • et al.
        The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men.
        Exp Mol Pathol. 2003; 74: 183-189
        • Konishi T.
        • Luo H.R.
        • Calvillo M.
        • Mayo M.S.
        • Lin K.M.
        • Wan Y.J.
        ADH1B*1, ADH1C*2, DRD2 (-141C Ins), and 5-HTTLPR are associated with alcoholism in Mexican American men living in Los Angeles.
        Alcohol Clin Exp Res. 2004; 28: 1145-1152
        • Montano Loza A.J.
        • Ramirez Iglesias M.T.
        • Perez Diaz I.
        • Cruz Castellanos S.
        • Garcia Andrade C.
        • Mora M.
        • et al.
        Association of alcohol-metabolizing genes with alcoholism in a Mexican Indian (Otomi) population.
        Alcohol. 2006; 39: 73-79
        • Ehlers C.L.
        • Montane-Jaime K.
        • Moore S.
        • Shafe S.
        • Joseph R.
        • Carr L.G.
        • et al.
        Association of the ADHIB*3 allele with alcohol-related phenotypes in Trinidad.
        Alcohol Clin Exp Res. 2007; 31: 216-220
        • Fu Q.
        • Heath A.C.
        • Bucholz K.K.
        • Nelson E.
        • Goldberg J.
        • Lyons M.J.
        • et al.
        Shared genetic risk of major depression, alcohol dependence, and marijuana dependence: Contribution of antisocial personality disorder in men.
        Arch Gen Psychiatry. 2002; 59: 1125-1132
        • Xian H.
        • Scherrer J.F.
        • Grant J.D.
        • Eisen S.A.
        • True W.R.
        • Jacob T.
        • et al.
        Genetic and environmental contributions to nicotine, alcohol and cannabis dependence in male twins.
        Addiction. 2008; 103: 1391-1398
        • True W.R.
        • Xian H.
        • Scherrer J.F.
        • Madden P.A.
        • Bucholz K.K.
        • Heath A.C.
        • et al.
        Common genetic vulnerability for nicotine and alcohol dependence in men.
        Arch Gen Psychiatry. 1999; 56: 655-661
        • World Health Organization
        World Health Organization's International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10).
        WHO, Geneva1992
      1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM). Washington, DC: American Psychiatric Publishing.

        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Luo X.
        • Kranzler H.R.
        • Zuo L.
        • Wang S.
        • Schork N.J.
        • Gelernter J.
        • et al.
        Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: Multiple significant associations with alcohol dependence.
        Am J Hum Genet. 2006; 78: 973-987
        • Edenberg H.J.
        The genetics of alcohol metabolism: Role of alcohol dehydrogenase and aldehyde dehydrogenase variants.
        Alcohol Res Health. 2007; 30: 5-13
        • Treutlein J.
        • Rietschel M.
        Genome-Wide Association Studies of Alcohol Dependence and Substance Use Disorders.
        Curr Psychiatry Rep. 2011;
        • Treutlein J.
        • Cichon S.
        • Ridinger M.
        • Wodarz N.
        • Soyka M.
        • Zill P.
        • et al.
        Genome-wide association study of alcohol dependence.
        Arch Gen Psychiatry. 2009; 66: 773-784
        • Bierut L.J.
        • Agrawal A.
        • Bucholz K.K.
        • Doheny K.F.
        • Laurie C.
        • Pugh E.
        • et al.
        A genome-wide association study of alcohol dependence.
        Proc Natl Acad Sci U S A. 2010; 107: 5082-5087
      2. Edenberg HJ, Koller DL, Xuei X, Wetherill L, McClintick JN, Almasy L, et al.: Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcohol Clin Exp Res 34:840–852.

        • Lind P.A.
        • Macgregor S.
        • Vink J.M.
        • Pergadia M.L.
        • Hansell N.K.
        • de Moor M.H.
        • et al.
        A genomewide association study of nicotine and alcohol dependence in Australian and Dutch populations.
        Twin Res Hum Genet. 2010; 13: 10-29
        • Drgon T.
        • Zhang P.W.
        • Johnson C.
        • Walther D.
        • Hess J.
        • Nino M.
        • et al.
        Genome wide association for addiction: Replicated results and comparisons of two analytic approaches.
        PLoS ONE. 2010; 5: e8832
        • Birley A.J.
        • James M.R.
        • Dickson P.A.
        • Montgomery G.W.
        • Heath A.C.
        • Martin N.G.
        • et al.
        ADH single nucleotide polymorphism associations with alcohol metabolism in vivo.
        Hum Mol Genet. 2009; 18: 1533-1542
      3. Zintzaras E: The generalized odds ratio as a measure of genetic risk effect in the analysis and meta-analysis of association studies. Stat Appl Genet Mol Biol 9:Article21.

        • Trikalinos T.A.
        • Salanti G.
        • Zintzaras E.
        • Ioannidis J.P.
        Meta-analysis methods.
        Adv Genet. 2008; 60: 311-334
        • Zintzaras E.
        • Lau J.
        Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches.
        J Clin Epidemiol. 2008; 61: 634-645
        • Zintzaras E.
        • Papathanasiou A.A.
        • Stefanidis I.
        Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis.
        Genet Med. 2009; 11: 695-706
        • Zintzaras E.
        • Raman G.
        • Kitsios G.
        • Lau J.
        Angiotensin-converting enzyme insertion/deletion gene polymorphic variant as a marker of coronary artery disease: A meta-analysis.
        Arch Intern Med. 2008; 168: 1077-1089
        • Minelli C.
        • Thompson J.R.
        • Abrams K.R.
        • Thakkinstian A.
        • Attia J.
        The choice of a genetic model in the meta-analysis of molecular association studies.
        Int J Epidemiol. 2005; 34: 1319-1328
        • Li D.
        • He L.
        Association study between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia: A meta-analysis.
        Schizophr Res. 2007; 96: 112-118
        • Li D.
        • He L.
        Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: A HuGE review and meta-analysis.
        Genet Med. 2007; 9: 4-8
        • Li D.
        • He L.
        G72/G30 genes and schizophrenia: A systematic meta-analysis of association studies.
        Genetics. 2007; 175: 917-922
        • Li D.
        • He L.
        Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior.
        Mol Psychiatry. 2007; 12: 47-54
        • Li D.
        • He L.
        Meta-study on association between the monoamine oxidase A gene (MAOA) and schizophrenia.
        Am J Med Genet B Neuropsychiatr Genet. 2008; 147B: 174-178
        • Yang S.J.
        • Yokoyama A.
        • Yokoyama T.
        • Huang Y.C.
        • Wu S.Y.
        • Shao Y.
        • et al.
        Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: A meta-analysis.
        World J Gastroenterol. 2010; 16: 4210-4220
        • Miyazaki H.
        • Yamaguchi Y.
        • Takehara T.
        Dental arch and palate in Taiwan aboriginals—Ami, Bunun, Paiwan and Rukai tribes.
        Arch Oral Biol. 1993; 38: 729-735