Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Haplotype association between GABAA receptor γ2 subunit gene (GABRG2) and methamphetamine use disorder

The Pharmacogenomics Journal volume 5, pages 89–95 (2005)Cite this article

Abstract

Psychostimulant use disorder and schizophrenia have a substantial genetic basis. Evidence from human and animal studies on the involvement of the γ-aminobutyric acid (GABA) system in methamphetamine (METH) use disorder and schizophrenia is mounting. As we tested for the association of the human GABAA receptor gamma 2 subunit gene (GABRG2) with each diagnostic group, we used a case–control design with a set of 178 subjects with METH use disorder, 288 schizophrenics and 288 controls. First, we screened 96 controls and identified six SNPs in GABRG2, three of whom we newly reported. Next, we selected two SNPs, 315C>T and 1128+99C>A, as representatives of the linkage disequilibrium blocks for further case–control association analysis. Although no associations were found in either allelic or genotypic frequencies, we detected a haplotypic association in GABRG2 with METH use disorder, but not with schizophrenia. This finding partly replicates a recent case–control study of GABRG2 in METH use disorder, and thus indicates that GABRG2 may be one of the susceptibility genes of METH use disorder.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

Abbreviations

METH:

methamphetamine

GABA:

γ-aminobutyric acid

GABRG2:

The human GABAA receptor gamma 2 subunit gene

GAD:

glutamic acid decarboxylase

PFC:

prefrontal cortex

LD:

linkage disequilibrium

DHPLC:

denaturing high-performance liquid chromatography

PCR-RFLP:

polymerase chain reaction-restriction fragment lengthpolymorphism

References

  1. Farrell M, Marsden J, Ali R, Ling W . Methamphetamine: drug use and psychoses becomes a major public health issue in the Asia Pacific region. Addiction 2002; 97: 771–772.

    Article  Google Scholar 

  2. UNDCP. United National International Drug Control Programme (UNDCP): World Drug Report. Oxford University Press: New York, 1997.

  3. Sato M, Chen CC, Akiyama K, Otsuki S . Acute exacerbation of paranoid psychotic state after long-term abstinence in patients with previous methamphetamine psychosis. Biol Psychiatry 1983; 18: 429–440.

    CAS  Google Scholar 

  4. Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N et al. Genetic influences on DSM-III-R drug abuse and dependence: a study of 3372 twin pairs. Am J Med Genet 1996; 67: 473–477.

    Article  CAS  Google Scholar 

  5. Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J et al. Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch Gen Psychiatry 1998; 55: 967–972.

    Article  CAS  Google Scholar 

  6. Kendler KS, Karkowski LM, Neale MC, Prescott CA . Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Arch Gen Psychiatry 2000; 57: 261–269.

    Article  CAS  Google Scholar 

  7. Spanagel R, Weiss F . The dopamine hypothesis of reward: past and current status. Trends Neurosci 1999; 22: 521–527.

    Article  CAS  Google Scholar 

  8. Gerasimov MR, Dewey SL . Gamma-vinyl gamma-aminobutyric acid attenuates the synergistic elevations of nucleus accumbens dopamine produced by a cocaine/heroin (speedball) challenge. Eur J Pharmacol 1999; 380: 1–4.

    Article  CAS  Google Scholar 

  9. Buck KJ, Finn DA . Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice. Addiction 2001; 96: 139–149.

    Article  CAS  Google Scholar 

  10. Lin SK, Chen CK, Ball D, Liu HC, Loh EW . Gender-specific contribution of the GABA(A) subunit genes on 5q33 in methamphetamine use disorder. Pharmacogenomics J 2003; 3: 349–355.

    Article  CAS  Google Scholar 

  11. Loh EW, Higuchi S, Matsushita S, Murray R, Chen CK, Ball D . Association analysis of the GABA(A) receptor subunit genes cluster on 5q33–34 and alcohol dependence in a Japanese population. Mol Psychiatry 2000; 5: 301–307.

    Article  CAS  Google Scholar 

  12. Loh EW, Smith II, Murray R, McLaughlin M, McNulty S, Ball D . Association between variants at the GABAAbeta2, GABAAalpha6 and GABAAgamma2 gene cluster and alcohol dependence in a Scottish population. Mol Psychiatry 2000; 5: 452.

    Article  CAS  Google Scholar 

  13. Sander T, Ball D, Murray R, Patel J, Samochowiec J, Winterer G et al. Association analysis of sequence variants of GABA(A) alpha6, beta2, and gamma2 gene cluster and alcohol dependence. Alcohol Clin Exp Res 1999; 23: 427–431.

    Article  CAS  Google Scholar 

  14. Simpson MD, Slater P, Deakin JF, Royston MC, Skan WJ . Reduced GABA uptake sites in the temporal lobe in schizophrenia. Neurosci Lett 1989; 107: 211–215.

    Article  CAS  Google Scholar 

  15. Reynolds GP, Czudek C, Andrews HB . Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia. Biol Psychiatry 1990; 27: 1038–1044.

    Article  CAS  Google Scholar 

  16. Sherman AD, Davidson AT, Baruah S, Hegwood TS, Waziri R . Evidence of glutamatergic deficiency in schizophrenia. Neurosci Lett 1991; 121: 77–80.

    Article  CAS  Google Scholar 

  17. Akbarian S, Huntsman MM, Kim JJ, Tafazzoli A, Potkin SG, Bunney Jr WE et al. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls. Cereb Cortex 1995; 5: 550–560.

    Article  CAS  Google Scholar 

  18. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA . Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 2000; 57: 237–245.

    Article  CAS  Google Scholar 

  19. Gluck MR, Thomas RG, Davis KL, Haroutunian V . Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients. Am J Psychiatry 2002; 159: 1165–1173.

    Article  Google Scholar 

  20. Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57: 1061–1069.

    Article  CAS  Google Scholar 

  21. Huntsman MM, Tran BV, Potkin SG, Bunney Jr WE, Jones EG . Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc Natl Acad Sci USA 1998; 95: 15066–15071.

    Article  CAS  Google Scholar 

  22. Kofuji P, Wang JB, Moss SJ, Huganir RL, Burt DR . Generation of two forms of the gamma-aminobutyric acidA receptor gamma 2-subunit in mice by alternative splicing. J Neurochem 1991; 56: 713–715.

    Article  CAS  Google Scholar 

  23. Whiting P, McKernan RM, Iversen LL . Another mechanism for creating diversity in gamma-aminobutyrate type A receptors: RNA splicing directs expression of two forms of gamma 2 phosphorylation site. Proc Natl Acad Sci USA 1990; 87: 9966–9970.

    Article  CAS  Google Scholar 

  24. Straub RE, MacLean CJ, O'Neill FA, Walsh D, Kendler KS . Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families. Mol Psychiatry 1997; 2: 148–155.

    Article  CAS  Google Scholar 

  25. Kendler KS, Myers JM, O'Neill FA, Martin R, Murphy B, MacLean CJ et al. Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 2000; 157: 402–408.

    Article  CAS  Google Scholar 

  26. Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68: 661–673.

    Article  CAS  Google Scholar 

  27. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  Google Scholar 

  28. Zhang L, Ashiya M, Sherman TG, Grabowski PJ . Essential nucleotides direct neuron-specific splicing of gamma 2 pre-mRNA. RNA 1996; 2: 682–698.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang L, Liu W, Grabowski PJ . Coordinate repression of a trio of neuron-specific splicing events by the splicing regulator PTB. RNA 1999; 5: 117–130.

    Article  CAS  Google Scholar 

  30. Ashiya M, Grabowski PJ . A neuron-specific splicing switch mediated by an array of pre-mRNA repressor sites: evidence of a regulatory role for the polypyrimidine tract binding protein and a brain-specific PTB counterpart. RNA 1997; 3: 996–1015.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jensen KB, Dredge BK, Stefani G, Zhong R, Buckanovich RJ, Okano HJ et al. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 2000; 25: 359–371.

    Article  CAS  Google Scholar 

  32. Dredge BK, Darnell RB . Nova regulates GABA(A) receptor gamma2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer. Mol Cell Biol 2003; 23: 4687–4700.

    Article  CAS  Google Scholar 

  33. Collins JS, Schwartz CE . Detecting polymorphisms and mutations in candidate genes. Am J Hum Genet 2002; 71: 1251–1252.

    Article  CAS  Google Scholar 

  34. Smoller JW, Lunetta KL, Robins J . Implications of comorbidity and ascertainment bias for identifying disease genes. Am J Med Genet 2000; 96: 817–822.

    Article  CAS  Google Scholar 

  35. Substance Abuse Department, W.H.O.. Amphetamine-Type Stimulants: A Report from the WHO Meeting on Amphetamine, MDMA and Other Psychostimulants, Geneva, 12–15 November 1996.

  36. Karler R, Calder LD, Thai DK, Bedingfield JB . The role of dopamine and GABA in the frontal cortex of mice in modulating a motor-stimulant effect of amphetamine and cocaine. Pharmacol Biochem Behav 1998; 60: 237–244.

    Article  CAS  Google Scholar 

  37. Winterer G, Smolka M, Samochowiec J, Mulert C, Ziller M, Mahlberg R et al. Association analysis of GABAAbeta2 and gamma2 gene polymorphisms with event-related prefrontal activity in man. Hum Genet 2000; 107: 513–518.

    Article  CAS  Google Scholar 

  38. Ujike H, Harano M, Inada T, Yamada M, Komiyama T, Sekine Y et al. Nine- or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis. Pharmacogenomics J 2003; 3: 242–247.

    Article  CAS  Google Scholar 

  39. Suzuki T, Iwata N, Kitamura Y, Kitajima T, Yamanouchi Y, Ikeda M et al. Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia. Am J Med Genet 2003; 121B: 7–13.

    Article  CAS  Google Scholar 

  40. Hoogendoorn B, Owen MJ, Oefner PJ, Williams N, Austin J, O'Donovan MC . Genotyping single nucleotide polymorphisms by primer extension and high performance liquid chromatography. Hum Genet 1999; 104: 89–93.

    Article  CAS  Google Scholar 

  41. Schneider S, Roessli D, Excoffier L . Arlequin: A software for population genetics data analysis. Ver. 2.000. 2000.

Download references

Acknowledgements

We gratefully acknowledge the helpful discussions with Dr J Ohashi on several points in the paper. We thank Ms Y Zusho and Ms M Miyata for their technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare.

Author information

Authors and Affiliations

  1. Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan

    T Nishiyama, M Ikeda, N Iwata, T Suzuki, T Kitajima & Y Yamanouchi

  2. Department of Psychiatry, Nagoya City University Medical School, Nagoya, Japan

    T Nishiyama & T Furukawa

  3. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M Ikeda, T Inada & N Ozaki

  4. Japanese Genetics Initiative for Drug Abuse (JGIDA), Japan

    N Iwata, Y Sekine, M Iyo, M Harano, T Komiyama, M Yamada, I Sora, H Ujike, T Inada & N Ozaki

  5. Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Y Sekine

  6. Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan

    M Iyo

  7. Department of Neuropsychiatry, Kurume University School of Medicine, Kurume, Japan

    M Harano

  8. Division of Psychiatry, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo, Japan

    T Komiyama

  9. Division of Psychogeriatrics, National Institute of Mental Health, National Center of Neurology and Psychiatry, Chiba, Japan

    M Yamada

  10. Department of Neuroscience, Division of Psychobiology, Tohoku University Graduate School of Medicine, Sendai, Japan

    I Sora

  11. Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

    H Ujike

Authors
  1. T Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Kitajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Yamanouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Sekine
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Iyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Harano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Komiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I Sora
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H Ujike
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T Inada
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. T Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. N Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N Iwata.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishiyama, T., Ikeda, M., Iwata, N. et al. Haplotype association between GABAA receptor γ2 subunit gene (GABRG2) and methamphetamine use disorder. Pharmacogenomics J 5, 89–95 (2005). https://doi.org/10.1038/sj.tpj.6500292

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500292

Keywords

This article is cited by

Search

Advanced search

Quick links