Journal of Neural Transmission

, Volume 119, Issue 4, pp 425–433 | Cite as

Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms

  • Ke-Sheng Wang
  • Xuefeng Liu
  • Qunyuan Zhang
  • Long-Yang Wu
  • Min Zeng
Basic Neurosciences, Genetics and Immunology - Original Article

Abstract

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10−4. The first best signal was rs770182 (p = 3.65 × 10−6) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10−4 (p = 7.15 × 10−6, 2.79 × 10−5 and 4.93 × 10−5, respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10−4 in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10−4 and 9.48 × 10−5, respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10−2) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.

Keywords

Alcohol dependence Withdrawal symptoms Genome-wide association Haplotype EFNA5 KDM4C 

Supplementary material

702_2011_729_MOESM1_ESM.xls (32 kb)
Supplementary material 1 (XLS 31 kb)
702_2011_729_MOESM2_ESM.xls (30 kb)
Supplementary material 2 (XLS 29 kb)

References

  1. 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 93:809–816PubMedCrossRefGoogle Scholar
  2. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  3. Becker HC (1998) Kindling in Alcohol Withdrawal. Alcohol Health & Research World (NIAAA) 22 (1). Archived from the original on 2010-11-14. http://pubs.niaaa.nih.gov/publications/arh22-1/25-34.pdf
  4. 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 107:5082–5087PubMedCrossRefGoogle Scholar
  5. Bleich S, Bönsch D, Rauh J, Bayerlein K, Fiszer R, Frieling H, Hillemacher T (2007) Association of the long allele of the 5-HTTLPR polymorphism with compulsive craving in alcohol dependence. Alcohol Alcohol 42:509–512PubMedGoogle Scholar
  6. Boffetta P, Hashibe M (2006) Alcohol and cancer. Lancet Oncol 7:149–156PubMedCrossRefGoogle Scholar
  7. Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P, Trichopoulos D, Ahrens W, Pigeot I, Merletti F, Richiardi L, Talamini R, Barzan L, Macfarlane GJ, Macfarlane TV, Holcátová I, Bencko V, Benhamou S, Bouchardy C, Kjaerheim K, Lowry R, Agudo A, Castellsagué X, Conway DI, McKinney PA, Znaor A, McCartan BE, Healy CM, Marron M, Brennan P (2009) Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project. Cancer Res 69:2956–2965PubMedCrossRefGoogle Scholar
  8. Cerretti DP, Copeland NG, Gilbert DJ, Jenkins NA, Kuefer MU, Valentine V, Shapiro DN, Cui X, Morris SW (1996) The gene encoding LERK-7 (EPLG7, Epl7), a ligand for the Eph-related receptor tyrosine kinases, maps to human chromosome 5 at band q21 and to mouse chromosome 17. Genomics 35:376–379PubMedCrossRefGoogle Scholar
  9. Dick DM, Plunkett J, Wetherill LF, Xuei X, Goate A, Hesselbrock V, Schuckit M, Crowe R, Edenberg HJ, Foroud T (2006) Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample. Alcohol Clin Exp Res 30:1101–1110PubMedCrossRefGoogle Scholar
  10. Druesne-Pecollo N, Tehard B, Mallet Y, Gerber M, Norat T, Hercberg S, Latino-Martel P (2009) Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol 10:173–180PubMedCrossRefGoogle Scholar
  11. Duan J, Sanders AR, Gejman PV (2010) Genome-wide approaches to schizophrenia. Brain Res Bull 83:93–102PubMedCrossRefGoogle Scholar
  12. Dudbridge F (2008) Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 66:87–98PubMedCrossRefGoogle Scholar
  13. Economidou D, Cippitelli A, Stopponi S, Braconi S, Clementi S, Ubaldi M, Martin-Fardon R, Weiss F, Massi M, Ciccocioppo R (2011) Activation of brain NOP receptors attenuates acute and protracted alcohol withdrawal symptoms in the rat. Alcohol Clin Exp Res 35:747–755PubMedCrossRefGoogle Scholar
  14. 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 34:840–852PubMedCrossRefGoogle Scholar
  15. Fehr C, Sander T, Tadic A, Lenzen KP, Anghelescu I, Klawe C, Dahmen N, Schmidt LG, Szegedi A (2006) Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis. Psychiatr Genet 16:9–17PubMedCrossRefGoogle Scholar
  16. Gizer IR, Edenberg HJ, Gilder DA, Wilhelmsen KC, Ehlers CL (2011) Association of alcohol dehydrogenase genes with alcohol-related phenotypes in a native American community sample. Alcohol Clin Exp Res 35:2008–2018Google Scholar
  17. Grant JD, Agrawal A, Bucholz KK, Madden PA, Pergadia ML, Nelson EC, Lynskey MT, Todd RD, Todorov AA, Hansell NK, Whitfield JB, Martin NG, Heath AC (2009) Alcohol consumption indices of genetic risk for alcohol dependence. Biol Psychiatry 66:795–800PubMedCrossRefGoogle Scholar
  18. Heath AC, Whitfield JB, Martin NG, Pergadia ML, Goate AM, Lind PA, McEvoy BP, Schrage AJ, Grant JD, Chou YL, Zhu R, Henders AK, Medland SE, Gordon SD, Nelson EC, Agrawal A, Nyholt DR, Bucholz KK, Madden PA, Montgomery GW (2011) A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. Biol Psychiatry 70:513-518Google Scholar
  19. Hoffmann T, Lange C (2006) P2BAT: a massive parallel implementation of PBAT for genome-wide association studies in R. Bioinformatics 22:3103–3105PubMedCrossRefGoogle Scholar
  20. Kantojärvi K, Onkamo P, Vanhala R, Alen R, Hedman M, Sajantila A, Nieminen-von Wendt T, Järvelä I (2010) Analysis of 9p24 and 11p12–13 regions in autism spectrum disorders: rs1340513 in the JMJD2C gene is associated with ASDs in Finnish sample. Psychiatr Genet 20:102–108PubMedGoogle Scholar
  21. Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ (1992) A population-based twin study of alcoholism in women. JAMA 268:1877–1882PubMedCrossRefGoogle Scholar
  22. 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 54:178–184PubMedCrossRefGoogle Scholar
  23. Kendler KS, Kalsi G, Holmans PA, Sanders AR, Aggen SH, Dick DM, Aliev F, Shi J, Levinson DF, Gejman PV (2011) Genomewide association analysis of symptoms of alcohol dependence in the molecular genetics of schizophrenia (MGS2) control sample. Alcohol Clin Exp Res 35:963–975PubMedCrossRefGoogle Scholar
  24. Kim JH, Karpyak VM, Biernacka JM, Nam HW, Lee MR, Preuss UW, Zill P, Yoon G, Colby C, Mrazek DA, Choi DS (2011) Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One 6(1):e16331PubMedCrossRefGoogle Scholar
  25. Kozlosky CJ, VandenBos T, Park L, Cerretti DP, Carpenter MK (1997) LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain. Cytokine 9:540–549PubMedCrossRefGoogle Scholar
  26. Lee YS, Choi SW, Han DH, Kim DJ, Joe KH (2009) Clinical manifestation of alcohol withdrawal symptoms related to genetic polymorphisms of two serotonin receptors and serotonin transporter. Eur Addict Res 15:39–46PubMedCrossRefGoogle Scholar
  27. Lesnick TG, Papapetropoulos S, Mash DC, Ffrench-Mullen J, Shehadeh L, de Andrade M, Henley JR, Rocca WA, Ahlskog JE, Maraganore DM (2007) A genomic pathway approach to a complex disease: axon guidance and Parkinson disease. PLoS Genet 3:e98PubMedCrossRefGoogle Scholar
  28. Lind PA, Macgregor S, Vink JM, Pergadia ML, Hansell NK, de Moor MH, Smit AB, Hottenga JJ, Richter MM, Heath AC, Martin NG, Willemsen G, de Geus EJ, Vogelzangs N, Penninx BW, Whitfield JB, Montgomery GW, Boomsma DI, Madden PA (2010) A genomewide association study of nicotine and alcohol dependence in Australian and Dutch populations. Twin Res Hum Genet 13:10–29PubMedCrossRefGoogle Scholar
  29. Liskow BI, Rinck C, Campbell J, DeSouza C (1989) Alcohol withdrawal in the elderly. J Stud Alcohol 50:414–421PubMedGoogle Scholar
  30. Liu G, Bollig-Fischer A, Kreike B, van de Vijver MJ, Abrams J, Ethier SP, Yang ZQ (2009) Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28:4491–4500PubMedCrossRefGoogle Scholar
  31. Longnecker MP (1995) Alcohol consumption and risk of cancer in humans: an overview. Alcohol 12:87–96PubMedCrossRefGoogle Scholar
  32. Lutz UC, Batra A, Kolb W, Machicao F, Maurer S, Köhnke MD (2006) Methylenetetrahydrofolate reductase C677T-polymorphism and its association with alcohol withdrawal seizure. Alcohol Clin Exp Res 30:1966–1971PubMedCrossRefGoogle Scholar
  33. Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1998) Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 5:277–286PubMedCrossRefGoogle Scholar
  34. Nelson EC, Heath AC, Bucholz KK, Madden PA, Fu Q, Knopik V, Lynskey MT, Lynskey MT, Whitfield JB, Statham DJ, Martin NG (2004) Genetic epidemiology of alcohol-induced blackouts. Arch Gen Psychiatry 61:257–263PubMedCrossRefGoogle Scholar
  35. Okubo T, Harada S (2001) Polymorphism of the neuropeptide Y gene: an association study with alcohol withdrawal. Alcohol Clin Exp Res 25(6 Suppl):59S–62SPubMedCrossRefGoogle Scholar
  36. Okubo T, Harada S, Higuchi S, Matsushita S (1999) Genetic association between alcohol withdrawal symptoms and polymorphism of CCK gene promoter. Alcohol Clin Exp Res 23(4 Suppl):11S–12SPubMedCrossRefGoogle Scholar
  37. Okubo T, Harada S, Higuchi S, Matsushita S (2003) Association analyses between polymorphisms of the phase II detoxification enzymes (GSTM1, NQO1, NQO2) and alcohol withdrawal symptoms. Alcohol Clin Exp Res 27(8 Suppl):68S–71SPubMedCrossRefGoogle Scholar
  38. Potkin SG, Guffanti G, Lakatos A, Turner JA, Kruggel F, Fallon JH, Saykin AJ, Orro A, Lupoli S, Salvi E, Weiner M, Macciardi F (2009) Alzheimer’s disease neuroimaging initiative. Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease. PLoS One 4(8):e6501PubMedCrossRefGoogle Scholar
  39. 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 156:34–40PubMedGoogle Scholar
  40. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRefGoogle Scholar
  41. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCrossRefGoogle Scholar
  42. Sander T, Samochowiec J, Ladehoff M, Smolka M, Peters C, Riess O, Rommelspacher H, Schmidt LG (1999) Association analysis of exonic variants of the gene encoding the GABAB receptor and alcohol dependence. Psychiatr Genet 9:69–73PubMedCrossRefGoogle Scholar
  43. Schmidt LG, Samochowiec J, Finckh U, Fiszer-Piosik E, Horodnicki J, Wendel B, Rommelspacher H, Hoehe MR (2002) Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. Drug Alcohol Depend 65:221–224PubMedCrossRefGoogle Scholar
  44. Schumann G, Coin LJ, Lourdusamy A, Charoen P, Berger KH, Stacey D, Desrivières S, Aliev FA, Khan AA, Amin N, Aulchenko YS, Bakalkin G, Bakker SJ, Balkau B, Beulens JW, Bilbao A, de Boer RA, Beury D, Bots ML, Breetvelt EJ, Cauchi S, Cavalcanti-Proença C, Chambers JC, Clarke TK, Dahmen N, de Geus EJ, Dick D, Ducci F, Easton A, Edenberg HJ, Esko T, Fernández-Medarde A, Foroud T, Freimer NB, Girault JA, Grobbee DE, Guarrera S, Gudbjartsson DF, Hartikainen AL, Heath AC, Hesselbrock V, Hofman A, Hottenga JJ, Isohanni MK, Kaprio J, Khaw KT, Kuehnel B, Laitinen J, Lobbens S, Luan J, Mangino M, Maroteaux M, Matullo G, McCarthy MI, Mueller C, Navis G, Numans ME, Núñez A, Nyholt DR, Onland-Moret CN, Oostra BA, O’Reilly PF, Palkovits M, Penninx BW, Polidoro S, Pouta A, Prokopenko I, Ricceri F, Santos E, Smit JH, Soranzo N, Song K, Sovio U, Stumvoll M, Surakk I, Thorgeirsson TE, Thorsteinsdottir U, Troakes C, Tyrfingsson T, Tönjes A, Uiterwaal CS, Uitterlinden AG, van der Harst P, van der Schouw YT, Staehlin O, Vogelzangs N, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Whitfield JB, Wichmann EH, Willemsen G, Witteman JC, Yuan X, Zhai G, Zhao JH, Zhang W, Martin NG, Metspalu A, Doering A, Scott J, Spector TD, Loos RJ, Boomsma DI, Mooser V, Peltonen L, Stefansson K, van Duijn CM, Vineis P, Sommer WH, Kooner JS, Spanagel R, Heberlein UA, Jarvelin MR, Elliott P (2011) Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption. Proc Natl Acad Sci USA 108:7119–7124PubMedCrossRefGoogle Scholar
  45. Soyka M, Preuss UW, Hesselbrock V, Zill P, Koller G, Bondy B (2008) GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence. J Psychiatr Res 42:184–191PubMedCrossRefGoogle Scholar
  46. Strat YL, Ramoz N, Schumann G, Gorwood P (2008) Molecular genetics of alcohol dependence and related endophenotypes. Curr Genomics 9:444–451PubMedCrossRefGoogle Scholar
  47. Sun HF, Chang YT, Fann CS, Chang CJ, Chen YH, Hsu YP, Yu WY, Cheng AT (2002) Association study of novel human serotonin 5-HT(1B) polymorphisms with alcohol dependence in Taiwanese Han. Biol Psychiatry 51:896–901PubMedCrossRefGoogle Scholar
  48. Sutrala SR, Goossens D, Williams NM, Heyrman L, Adolfsson R, Norton N, Buckland PR, Del-Favero J (2007) Gene copy number variation in schizophrenia. Schizophr Res 96:93–99PubMedCrossRefGoogle Scholar
  49. Treutlein J, Cichon S, Ridinger M, Wodarz N, Soyka M, Zill P, Maier W, Moessner R, Gaebel W, Dahmen N, Fehr C, Scherbaum N, Steffens M, Ludwig KU, Frank J, Wichmann HE, Schreiber S, Dragano N, Sommer WH, Leonardi-Essmann F, Lourdusamy A, Gebicke-Haerter P, Wienker TF, Sullivan PF, Nothen MM, Kiefer F, Spanagel R, Mann K, Rietschel M (2009) Genome-wide association study of alcohol dependence. Arch Gen Psychiatry 66:773–784PubMedCrossRefGoogle Scholar
  50. Wang KS, Liu X, Zhang Q, Pan Y, Aragam N, Zeng M (2011) Meta-analysis of two genome-wide association studies identifies 3 new loci for alcohol dependence. J Psychiatr Res 45:1419–1425Google Scholar
  51. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678CrossRefGoogle Scholar
  52. Wetherill L, Schuckit MA, Hesselbrock V, Xuei X, Liang T, Dick DM, Kramer J, Nurnberger JI Jr, Tischfield JA, Porjesz B, Edenberg HJ, Foroud T (2008) Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence. Alcohol Clin Exp Res 32:2031–2040PubMedCrossRefGoogle Scholar
  53. Wilkinson DG (2001) Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2:155–164PubMedCrossRefGoogle Scholar
  54. Xuei X, Flury-Wetherill L, Dick D, Goate A, Tischfield J, Nurnberger J Jr, Schuckit M, Kramer J, Kuperman S, Hesselbrock V, Porjesz B, Foroud T, Edenberg HJ (2010) GABRR1 and GABRR2, encoding the GABA-A receptor subunits rho1 and rho2, are associated with alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 153B:418–427PubMedGoogle Scholar
  55. Yang ZQ, Imoto I, Fukuda Y, Pimkhaokham A, Shimada Y, Imamura M, Sugano S, Nakamura Y, Inazawa J (2000) Identification of a novel gene, GASC1, within an amplicon at 9p23–24 frequently detected in esophageal cancer cell lines. Cancer Res 60:4735–4739PubMedGoogle Scholar
  56. Zlojutro M, Manz N, Rangaswamy M, Xuei X, Flury-Wetherill L, Koller D, Bierut LJ, Goate A, Hesselbrock V, Kuperman S, Nurnberger J Jr, Rice JP, Schuckit MA, Foroud T, Edenberg HJ, Porjesz B, Almasy L (2011) Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 156B(1):44–58PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ke-Sheng Wang
    • 1
  • Xuefeng Liu
    • 1
  • Qunyuan Zhang
    • 2
  • Long-Yang Wu
    • 3
  • Min Zeng
    • 1
  1. 1.Department of Biostatistics and Epidemiology, College of Public HealthEast Tennessee State UniversityJohnson CityUSA
  2. 2.Division of Statistical GenomicsWashington University School of MedicineSt. LouisUSA
  3. 3.Department of Statistics and Actuarial ScienceUniversity of WaterlooWaterlooCanada

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