ABSTRACT
Family and twins studies have suggested that genetic factors are involved in the development of substance use disorders. Several unrelated case/control association studies have reported associations of the GABAA subunit genes on 5q33 with the development of alcohol dependence. We hypothesized that these particular GABAA subunit genes also contribute to the development of methamphetamine use disorder. To test our hypothesis, we recruited cases using a series of questionnaires. Among the polymorphic SNPs, significant differences between cases and controls were identified in the female sample in the rs2279020 of the GABAAα1 subunit gene, and the novel SNP rs4480617 in the GABAAγ2 subunit gene. No associations were found in the male sample. Further haplotype analysis identified several marker blocks significantly associated with methamphetamine use disorder in females; each block consists of the rs4480617. Our study provides preliminary evidence that the GABAA subunit genes on 5q33 may preferentially contribute to methamphetamine use disorder in females.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gossop M Living with Drugs. Brookfield: Ashgate 1993.
King GR, Ellinwood EHJ . Amphetamines and other stimulants. In: Lowinson JH, Ruiz P, Millman RB, Langrod JG (eds). Substance Abuse: A Comprehensive Textbook. Baltimore: Williams & Wilkins 199: 24–270.
Merikangas KR, Stolar M, Stevens DE, Goulet J, Preisig MA, Fenton B . Familial transmission of substance use disorders. Arch Gen Psychiatry 1998; 55: 973–979.
Grove WM, Eckert ED, Heston L, Bouchard Jr TJ, Segal N, Lykken DT . Heritability of substance abuse and antisocial behavior: a study of monozygotic twins reared apart. Biol Psychiatry 1990; 27: 1293–1304.
Perkins KA, Simpson JC, Tsuang MT . Ten-year follow-up of drug abusers with acute or chronic psychosis. Hosp Community Psychiatry 1986; 37: 481–484.
Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N . Genetic influences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. Am J Med Genet 1996; 67: 473–477.
Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J . Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch Gen Psychiatry 1998; 55: 967–972.
Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G . Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 1997; 90: 991–1001.
Reynolds DS, O'Meara GF, Newman RJ, Bromidge FA, Atack JR, Whiting PJ . GABA(A) alpha1 subunit knock-out mice do not show a hyperlocomotor response following amphetamine or cocaine treatment. Neuropharmacology 2003; 44: 190–198.
Sery O, Vojtova V, Zvolsky P . The association study of DRD2, ACE and AGT gene polymorphisms and metamphetamine dependence. Physiol Res 2001; 50: 43–50.
Tsai SJ, Cheng CY, Shu LR, Yang CY, Pan CW, Liou YJ . No association for D2 and D4 dopamine receptor polymorphisms and methamphetamine abuse in Chinese males. Psychiatry Genet 2002; 12: 29–33.
Hong CJ, Cheng CY, Shu LR, Yang CY, Tsai SJ . Association study of the dopamine and serotonin transporter genetic polymorphisms and methamphetamine abuse in Chinese males. J Neural Transm 2003; 110: 345–351.
Enna SJ, Snyder SH . Properties of gamma-aminobutyric acid (GABA) receptor binding in rat brain synaptic membrane fractions. Brain Res 1975; 100: 81–97.
Enna SJ, Snyder SH . Influences ions, enzymes, and detergents on gamma-aminobutyric acid-receptor binding in synaptic membranes of rat brain. Mol Pharmacol 1977; 13: 442–453.
Zukin SR, Young AB, Snyder SH . Gamma-aminobutyric acid binding to receptor sites in the rat central nervous system. Proc Natl Acad Sci USA 1974; 71: 4802–4807.
Peck Jr EJ, Schaeffer JM, Clark JH . Gamma-aminobutyric acid, bicuculline, and post-synaptic binding sites. Biochem Biophys Res Commun 1973; 52: 394–400.
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.
Loh EW, Smith I, 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 1999; 4: 539–544.
Sander T, Ball D, Murray R, Patel J, Samochowiec J, Winterer G . 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.
Schuckit MA, Mazzanti C, Smith TL, Ahmed U, Radel M, Iwata N . Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol Psychiatry 1999; 45: 647–651.
Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud'homme JF . First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat Genet 2001; 28: 46–48.
Harkin LA, Bowser DN, Dibbens LM, Singh R, Phillips F, Wallace RH . Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet 2002; 70: 530–536.
Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M . Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 2002; 31: 184–189.
Wallace RH, Scheffer IE, Barnett S, Richards M, Dibbens L, Desai RR . Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 2001; 68: 859–865.
Song J, Koller DL, Foroud T, Carr K, Zhao J, Rice J . Association of GABAA receptors and alcohol dependence and the effects of genetic imprinting. Am J Med Genet 2003; 117B: 39–45.
Buck KJ, Metten P, Belknap JK, Crabbe JC . Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J Neurosci 1997; 17: 3946–3955.
Sur C, Wafford KA, Reynolds DS, Hadingham KL, Bromidge F, Macaulay A . Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J Neurosci 2001; 21: 3409–3418.
Kralic JE, Korpi ER, O'Buckley TK, Homanics GE, Morrow AL . Molecular and pharmacological characterization of GABA(A) receptor alpha1 subunit knockout mice. J Pharmacol Exp Ther 2002; 302: 1037–1045.
Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP . Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 1999; 2: 833–839.
McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR . Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci 2000; 3: 587–592.
Makela R, Wong G, Luddens H, Korpi ER . Phenotypic and genotypic analysis of rats with cerebellar GABAA receptors composed from mutant and wild-type alpha 6 subunits. J Neurochem 1995; 65: 2401–2408.
Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM . Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 1999; 401: 796–800.
Reynolds DS, O'Meara GF, Newman RJ, Bromidge FA, Atack JR, Whiting PJ . GABA(A) alpha 1 subunit knock-out mice do not show a hyperlocomotor response following amphetamine or cocaine treatment. Neuropharmacology 2003; 44: 190–198.
Homanics GE, Le NQ, Kist F, Mihalek R, Hart AR, Quinlan JJ . Ethanol tolerance and withdrawal responses in GABA(A) receptor alpha 6 subunit null allele mice and in inbred C57BL/6J and strain 129/SvJ mice. Alcohol Clin Exp Res 1998; 22: 259–265.
Homanics GE, Ferguson C, Quinlan JJ, Daggett J, Snyder K, Lagenaur C . Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol Pharmacol 1997; 51: 588–596.
Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ . Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther 2003; 304: 30–36.
Korpi ER, Seeburg PH . Natural mutation of GABAA receptor alpha 6 subunit alters benzodiazepine affinity but not allosteric GABA effects. Eur J Pharmacol 1993; 247: 23–27.
Homanics GE, Harrison NL, Quinlan JJ, Krasowski MD, Rick CE, de Blas AL . Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the gamma2 subunit of the gamma-aminobutyrate type A receptor. Neuropharmacology 1999; 38: 253–265.
Chen CK, Lin SK, Sham PC, Ball D, Loh EW, Hsiao CC . Premorbid characteristics and comorbidity of methamphetamine users with and without psychosis. Psychol Med 2003; In print.
Kandall SR . Drug addiction research and the health of women. In: Wetherington CL, Roman AB (eds). Women and Addiction in the United States, 1920 to the Present. National Institute of Drug Abuse: Rockville, MD 1998: 98–4298.
Chong MY, Chan KW, Cheng AT . Substance use disorders among adolescents in Taiwan: prevalence, sociodemographic correlates and psychiatric co-morbidity. Psychol Med 1999; 29: 1387–1396.
Chen CK, Shu LW, Liang PL, Hung TM, Lin SK . Drug use patterns and gender differences among heroin addicts hospitalized for detoxification. Changgeng Yi Xue Za Zhi 1998; 21: 172–178.
Gerner RH . Systematic treatment approach to depression and treatment-resistant depression. Psychiatry Ann 1983; 13: 37–49.
Bell IR, Baldwin CM, Schwartz GE . Sensitization studies in chemically intolerant individuals: implications for individual difference research. Ann NY Acad Sci 2001; 933: 38–47.
Hongyo T, Buzard GS, Calvert RJ, Weghorst CM . Cold SSCP': a simple, rapid and non-radioactive method for optimized single-strand conformation polymorphism analyses. Nucleic Acids Res 1993; 21: 3637–3642.
Guo SW, Thompson EA . Performing the exact test of Hardy–Weinberg proportion for multiple alleles. Biometrics 1992; 48: 361–372.
Ohashi J, Yamamoto S, Tsuchiya N, Hatta Y, Komata T, Matsushita M . Comparison of statistical power between 2*2 allele frequency and allele positivity tables in case–control studies of complex disease genes. Ann Hum Genet 2001; 65: 197–206.
Zhao JH, Sham PC . Faster haplotype frequency estimation using unrelated subjects. Hum Hered 2002; 53: 36–41.
Kaboev OK, Luchkina LA, Tret'iakov AN, Bahrmand AR . PCR hot start using primers with the structure of molecular beacons (hairpin-like structure). Nucleic Acids Res 2000; 28: E94.
Acknowledgements
This study was supported by the National Science Council, Taiwan (Grant Number: NSC 90-2314-B-109-003 and NGC 91-2314-B-109-002). We thank Professor Robin Murray at the Institute of Psychiatry, London, for his financial support in this study and advice in the preparation of this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lin, SK., Chen, CK., Ball, D. et al. Gender-specific contribution of the GABAA subunit genes on 5q33 in methamphetamine use disorder. Pharmacogenomics J 3, 349–355 (2003). https://doi.org/10.1038/sj.tpj.6500203
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.tpj.6500203
Keywords
This article is cited by
-
Variants in GABBR1 Gene Are Associated with Methamphetamine Dependence and Two Years’ Relapse after Drug Rehabilitation
Journal of Neuroimmune Pharmacology (2018)
-
Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder
Neuropsychopharmacology (2014)
-
Testing allele homogeneity: the problem of nested hypotheses
BMC Genetics (2012)
-
The adenosine A2A receptor is associated with methamphetamine dependence/psychosis in the Japanese population
Behavioral and Brain Functions (2010)
-
Haplotype association between GABAA receptor γ2 subunit gene (GABRG2) and methamphetamine use disorder
The Pharmacogenomics Journal (2005)