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Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication

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Abstract

Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case–control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10−21, OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.

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References

  • Baik I, Cho NH, Kim SH, Han BG, Shin C (2011) Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr 93(4):809–816

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265

    Article  PubMed  CAS  Google Scholar 

  • Bierut LJ, Agrawal A, Bucholz KK, Doheny KF, Laurie C, Pugh E, Fisher S, Fox L, Howells W, Bertelsen S, Hinrichs AL, Almasy L, Breslau N, Culverhouse RC, Dick DM, Edenberg HJ, Foroud T, Grucza RA, Hatsukami D, Hesselbrock V, Johnson EO, Kramer J, Krueger RF, Kuperman S, Lynskey M, Mann K, Neuman RJ, Nothen MM, Nurnberger JI Jr, Porjesz B, Ridinger M, Saccone NL, Saccone SF, Schuckit MA, Tischfield JA, Wang JC, Rietschel M, Goate AM, Rice JP (2010) A genome-wide association study of alcohol dependence. Proc Natl Acad Sci USA 107(11):5082–5087

    Article  PubMed  CAS  Google Scholar 

  • Birley AJ, James MR, Dickson PA, Montgomery GW, Heath AC, Whitfield JB, Martin NG (2008) Association of the gastric alcohol dehydrogenase gene ADH7 with variation in alcohol metabolism. Hum Mol Genet 17(2):179–189

    Article  PubMed  CAS  Google Scholar 

  • Chen CC, Lu RB, Chen YC, Wang MF, Chang YC, Li TK, Yin SJ (1999) Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 65(3):795–807

    Article  PubMed  CAS  Google Scholar 

  • Choi IG, Son HG, Yang BH, Kim SH, Lee JS, Chai YG, Son BK, Kee BS, Park BL, Kim LH, Choi YH, Shin HD (2005) Scanning of genetic effects of alcohol metabolism gene (ADH1B and ADH1C) polymorphisms on the risk of alcoholism. Hum Mutat 26(3):224–234

    Article  PubMed  CAS  Google Scholar 

  • Edenberg HJ (2007) The genetics of alcohol metabolism: role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Res Health 30(1):5–13

    PubMed  Google Scholar 

  • Edenberg HJ, Xuei X, Chen HJ, Tian H, Wetherill LF, Dick DM, Almasy L, Bierut L, Bucholz KK, Goate A, Hesselbrock V, Kuperman S, Nurnberger J, Porjesz B, Rice J, Schuckit M, Tischfield J, Begleiter H, Foroud T (2006) Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis. Hum Mol Genet 15(9):1539–1549

    Article  PubMed  CAS  Google Scholar 

  • Edenberg HJ, Koller DL, Xuei X, Wetherill L, McClintick JN, Almasy L, Bierut LJ, Bucholz KK, Goate A, Aliev F, Dick D, Hesselbrock V, Hinrichs A, Kramer J, Kuperman S, Nurnberger JI Jr, Rice JP, Schuckit MA, Taylor R, Todd Webb B, Tischfield JA, Porjesz B, Foroud T (2010) Genome-wide association study of alcohol dependence implicates a region on chromosome 11. Alcohol Clin Exp Res 34(5):840–852

    Article  PubMed  CAS  Google Scholar 

  • Enoch MA, Goldman D (2002) Problem drinking and alcoholism: diagnosis and treatment. Am Fam Physician 65(3):441–448

    PubMed  Google Scholar 

  • Fan JB, Gunderson KL, Bibikova M, Yeakley JM, Chen J, Wickham Garcia E, Lebruska LL, Laurent M, Shen R, Barker D (2006) Illumina universal bead arrays. Methods Enzymol 410:57–73

    Article  PubMed  CAS  Google Scholar 

  • Farres J, Moreno A, Crosas B, Peralba JM, Allali-Hassani A, Hjelmqvist L, Jornvall H, Pares X (1994) Alcohol dehydrogenase of class IV (sigma sigma-ADH) from human stomach: cDNA sequence and structure/function relationships. Eur J Biochem 224(2):549–557

    Article  PubMed  CAS  Google Scholar 

  • Frank J, Cichon S, Treutlein J, Ridinger M, Mattheisen M, Hoffmann P, Herms S, Wodarz N, Soyka M, Zill P, Maier W, Mossner R, Gaebel W, Dahmen N, Scherbaum N, Schmal C, Steffens M, Lucae S, Ising M, Muller-Myhsok B, Nothen MM, Mann K, Kiefer F, Rietschel M (2011) Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster. Addict Biol 17(1):171–180

    Article  PubMed  Google Scholar 

  • Han Y, Gu S, Oota H, Osier MV, Pakstis AJ, Speed WC, Kidd JR, Kidd KK (2007) Evidence of positive selection on a class I ADH locus. Am J Hum Genet 80(3):441–456

    Article  PubMed  CAS  Google Scholar 

  • Higuchi S (1994) Polymorphisms of ethanol metabolizing enzyme genes and alcoholism. Alcohol Alcohol Suppl 2:29–34

    PubMed  CAS  Google Scholar 

  • Hurley TD, Edenberg HJ, Li TK (2002) Pharmacogenomics of alcoholism. In: Licinio J, Wong ML (eds) Pharmacogenomics: the search for individualized therapies. Wiley, Weinheim, pp 417–441

    Google Scholar 

  • Ji YB, Tae K, Ahn TH, Lee SH, Kim KR, Park CW, Park BL, Shin HD (2011) ADH1B and ALDH2 polymorphisms and their associations with increased risk of squamous cell carcinoma of the head and neck in the Korean population. Oral Oncol 47(7):583–587

    Article  PubMed  CAS  Google Scholar 

  • Joe KH, Kim DJ, Park BL, Yoon S, Lee HK, Kim TS, Cheon YH, Gwon DH, Cho SN, Lee HW, Namgung S, Shin HD (2008) Genetic association of DRD2 polymorphisms with anxiety scores among alcohol-dependent patients. Biochem Biophys Res Commun 371(4):591–595

    Article  PubMed  CAS  Google Scholar 

  • Kaiser R, Holmquist B, Vallee BL, Jornvall H (1991) Human class III alcohol dehydrogenase/glutathione-dependent formaldehyde dehydrogenase. J Protein Chem 10(1):69–73

    Article  PubMed  CAS  Google Scholar 

  • Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ (1992) A population-based twin study of alcoholism in women. JAMA 268(14):1877–1882

    Article  PubMed  CAS  Google Scholar 

  • Kendler KS, Neale MC, Heath AC, Kessler RC, Eaves LJ (1994) A twin-family study of alcoholism in women. Am J Psychiatry 151(5):707–715

    PubMed  CAS  Google Scholar 

  • Kendler KS, Prescott CA, Neale MC, Pedersen NL (1997) Temperance board registration for alcohol abuse in a national sample of Swedish male twins, born 1902 to 1949. Arch Gen Psychiatry 54(2):178–184

    Article  PubMed  CAS  Google Scholar 

  • Kim DJ, Choi IG, Park BL, Lee BC, Ham BJ, Yoon S, Bae JS, Cheong HS, Shin HD (2008) Major genetic components underlying alcoholism in Korean population. Hum Mol Genet 17(6):854–858

    Article  PubMed  CAS  Google Scholar 

  • Lee SL, Hoog JO, Yin SJ (2004) Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism. Pharmacogenetics 14(11):725–732

    Article  PubMed  CAS  Google Scholar 

  • Li TK, Yin SJ, Crabb DW, O’Connor S, Ramchandani VA (2001) Genetic and environmental influences on alcohol metabolism in humans. Alcohol Clin Exp Res 25(1):136–144

    Article  PubMed  CAS  Google Scholar 

  • Li H, Mukherjee N, Soundararajan U, Tarnok Z, Barta C, Khaliq S, Mohyuddin A, Kajuna SL, Mehdi SQ, Kidd JR, Kidd KK (2007) Geographically separate increases in the frequency of the derived ADH1B*47His allele in eastern and western Asia. Am J Hum Genet 81(4):842–846

    Article  PubMed  CAS  Google Scholar 

  • Lin CH, Yeakley JM, McDaniel TK, Shen R (2009) Medium- to high-throughput SNP genotyping using VeraCode microbeads. Methods Mol Biol 496:129–142

    Article  PubMed  CAS  Google Scholar 

  • Luo X, Kranzler HR, Zuo L, Yang BZ, Lappalainen J, Gelernter J (2005) ADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studies. Pharmacogenet Genomics 15(11):755–768

    Article  PubMed  CAS  Google Scholar 

  • Nakamura K, Iwahashi K, Matsuo Y, Miyatake R, Ichikawa Y, Suwaki H (1996) Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2*2. I. A comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P-4502E1 between alcoholics and nonalcoholics. Alcohol Clin Exp Res 20(1):52–55

    Article  PubMed  CAS  Google Scholar 

  • Osier M, Pakstis AJ, Kidd JR, Lee JF, Yin SJ, Ko HC, Edenberg HJ, Lu RB, Kidd KK (1999) Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism. Am J Hum Genet 64(4):1147–1157

    Article  PubMed  CAS  Google Scholar 

  • Osier MV, Pakstis AJ, Soodyall H, Comas D, Goldman D, Odunsi A, Okonofua F, Parnas J, Schulz LO, Bertranpetit J, Bonne-Tamir B, Lu RB, Kidd JR, Kidd KK (2002) A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. Am J Hum Genet 71(1):84–99

    Article  PubMed  CAS  Google Scholar 

  • Oze I, Matsuo K, Suzuki T, Kawase T, Watanabe M, Hiraki A, Ito H, Hosono S, Ozawa T, Hatooka S, Yatabe Y, Hasegawa Y, Shinoda M, Kiura K, Tajima K, Tanimoto M, Tanaka H (2009) Impact of multiple alcohol dehydrogenase gene polymorphisms on risk of upper aerodigestive tract cancers in a Japanese population. Cancer Epidemiol Biomarkers Prev 18(11):3097–3102

    Article  PubMed  CAS  Google Scholar 

  • Peng Y, Shi H, Qi XB, Xiao CJ, Zhong H, Ma RL, Su B (2010) The ADH1B Arg47His polymorphism in East Asian populations and expansion of rice domestication in history. BMC Evol Biol 10:15

    Article  PubMed  Google Scholar 

  • Prescott CA, Kendler KS (1999) Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 156(1):34–40

    PubMed  CAS  Google Scholar 

  • Shen YC, Fan JH, Edenberg HJ, Li TK, Cui YH, Wang YF, Tian CH, Zhou CF, Zhou RL, Wang J, Zhao ZL, Xia GY (1997) Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol Clin Exp Res 21(7):1272–1277

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68(4):978–989

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi F, Isono M, Nabika T, Katsuya T, Sugiyama T, Yamaguchi S, Kobayashi S, Ogihara T, Yamori Y, Fujioka A, Kato N (2011) Confirmation of ALDH2 as a major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ J 75(4):911–918

    Article  PubMed  CAS  Google Scholar 

  • Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, Lin YT, Lu RB, Yin SJ (1991) Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 48(4):677–681

    PubMed  CAS  Google Scholar 

  • Tolstrup JS, Nordestgaard BG, Rasmussen S, Tybjaerg-Hansen A, Gronbaek M (2008) Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes. Pharmacogenomics J 8(3):220–227

    Article  PubMed  CAS  Google Scholar 

  • Whitfield JB (2002) Alcohol dehydrogenase and alcohol dependence: variation in genotype-associated risk between populations. Am J Hum Genet 71(5):1247–1250 author reply 1250–1241

    Article  PubMed  CAS  Google Scholar 

  • Zuo L, Zhang CK, Wang F, Li CS, Zhao H, Lu L, Zhang XY, Lu L, Zhang H, Zhang F, Krystal JH, Luo X (2011) A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study. PLoS One 6(11):e26726

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (Grant Number A084589).

Conflict of interest

Byung-Lae Park, Hyun Sub Cheong and Lyoung Hyo Kim are employees, and Hyoung Doo Shin is a CEO of SNP Genetics, Inc., which is located at #TE1007, Teilhard hall, Sogang University, Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea. This company provided the iScan scanner instrument and BeadStudio 3.0 software used in the research. They also were involved in the study design, data collection and analysis, decision to publish and preparation of the manuscript. However, these competing interests do not alter our adherence to all the Human Genetics policies. No other relevant competing interests are declared.

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Authors and Affiliations

  1. Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Republic of Korea

    Byung Lae Park, Hyun Sub Cheong, Lyoung Hyo Kim & Hyoung Doo Shin

  2. Department of Neuropsychiatry, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi Province, Republic of Korea

    Jee Wook Kim

  3. Hallym University Burn Institute, Seoul, Republic of Korea

    Jee Wook Kim, Boung Chul Lee, Cheong Hoon Seo & Ihn-Geun Choi

  4. Department of Neuropsychiatry, Hangang Sacred Heart Hospital, Hallym University, Seoul, Republic of Korea

    Boung Chul Lee

  5. Department of Rehabilitation Medicine, Hangang Sacred Heart Hospital, Hallym University, Seoul, Republic of Korea

    Cheong Hoon Seo

  6. Department of Anatomy and Neurobiology, Institute of Epilepsy Research, Hallym University, College of Medicine, Chuncheon, Republic of Korea

    Tae-Cheon Kang

  7. Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea

    Lyoung Hyo Kim, Young-Woo Nam, Goon-Bo Kim & Hyoung Doo Shin

  8. Department of Neuropsychiatry, Hallym University Kangnam Sacred Heart Hospital, 948-1 Daerim 1-Dong, Yeongdeungpo-Gu, Seoul, 150-950, Republic of Korea

    Ihn-Geun Choi

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  1. Byung Lae Park
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Correspondence to Hyoung Doo Shin or Ihn-Geun Choi.

Additional information

B. L. Park and J. W. Kim contributed equally to this work.

Electronic supplementary material

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The supplementary data below include one figure and four tables.

Supplementary Figure 1. Haplotype and linkage disequilibrium among polymorphisms in the ADH gene cluster (4q22-24).

Supplementary Table 1. Genome-wide association results of alcohol dependence including nominal association (p < 0.01) in a Korean population

Supplementary Table 2. Frequencies of polymorphisms in the ADH gene cluster in second follow-up study of Korean populations (n = 975).

Supplementary Table 3. Referent analysis of ADH1B rs1229984 (H48R) with the risk of alcohol dependence (n = 975).

Supplementary Table 4. Association analysis of haplotypes in the ADH gene cluster with risk of alcoholism and conditional analysis of the subjects selected for follow-up study.

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Supplementary material 2 (TIFF 3083 kb)

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Park, B.L., Kim, J.W., Cheong, H.S. et al. Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication. Hum Genet 132, 657–668 (2013). https://doi.org/10.1007/s00439-013-1281-8

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