Behavior Genetics

, Volume 36, Issue 5, pp 640–650

Association of GABRA2 with Drug Dependence in the Collaborative Study of the Genetics of Alcoholism Sample

  • Arpana Agrawal
  • Howard J. Edenberg
  • Tatiana Foroud
  • Laura J. Bierut
  • Gerald Dunne
  • Anthony L. Hinrichs
  • John I. Nurnberger
  • Raymond Crowe
  • Samuel Kuperman
  • Marc A. Schuckit
  • Henri Begleiter
  • Bernice Porjesz
  • Danielle M. Dick
Article

Abstract

Results from twin studies suggest that overlapping genetic factors influence alcohol dependence and illicit drug dependence. Using data from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined the association between 69 SNPs in the GABAA receptor gene cluster on chromosome 4 and marijuana and illicit drug dependence, individually, and as co-occurring phenotypes with alcohol dependence. Results suggested association between marijuana dependence and illicit drug dependence with SNPs in the GABRA2 gene. Interestingly, the evidence for association previously observed with alcohol dependence came only from individuals with comorbid illicit drug dependence. There was no association with other genes in the GABAA cluster on chromosome 4 with illicit drug dependence.

Keywords

Alcoholism association analyses COGA drug dependence GABRA2 PDT 

References

  1. Agrawal, A., Heath, A. C., Pergadia, M., Saccone, S., Dick, D. M., Grant, J. D., Lynskey, M., Rice, J., Todorov, A. A., Wang, J., Martin, N. G., and Madden, P. (2005a). Linkage signals for illicit drug phenotypes: Results from the Nicotine Addiction Genetics Project. Behav. Genet. 6: 793Google Scholar
  2. Agrawal A., Neale M., Jacobson K., Prescott C. A. and Kendler K. S. (2005b). Illicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach. Addict Behav. 30:1043–1048CrossRefGoogle Scholar
  3. American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders. Washington, DC, American Psychiatric AssociationGoogle Scholar
  4. Bierut L. J., Dinwiddie S. H., Begleiter H., Crowe R. R., Hesselbrock V., Nurnberger J. I., Jr., Porjesz B., Schuckit M. A., and Reich T. (1998). Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch. Gen. Psych. 55:982–988CrossRefGoogle Scholar
  5. Boehnke M. (1991). Allele frequency estimation from data on relatives. Am. J. Hum. Genet. 48:22–25PubMedGoogle Scholar
  6. Bucholz K. K., Cadoret R. J., Cloninger R. C., Dinwiddie S. H., Hesselbrock V., Nurnberger J. I., Reich T., Schmidt I., and Schuckit M. A. (1994). A new, semi-structured psychiatric interview for use in genetic linkage studies. J. Stud. Alcohol 55:149–158PubMedGoogle Scholar
  7. Buck K. J. and Finn D. A. (2001). Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice. Addiction 96:139–149PubMedCrossRefGoogle Scholar
  8. Covault J., Gelernter J., Hesselbrock V., Nellissery M., and Kranzler H. R. (2004). Allelic and haplotypic association of GABRA2 with alcohol dependence. Am J Med Genet. B Neuropsychiatr. Genet. 129:104–109CrossRefGoogle Scholar
  9. Degenhardt L., Hall W. and Lynskey M. (2001). Alcohol, cannabis and tobacco use among Australians: a comparison of their associations with other drug use and use disorders, affective and anxiety disorders, and psychosis. Addiction 96:1603–1614PubMedCrossRefGoogle Scholar
  10. Dick, D. M., Bierut, L. J., Hinrichs, A. L., Fox, L., Bucholz, K., Kramer, J. R., Kuperman, S., Hesselbrock, M., Schuckit, M., Almasy, L., Tischfield, J. A., Porjesz, B., Begleiter, H., Nurnberger, J. I., Xuei, X., Edenberg, H. J., and Foroud, T. (2006). The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across different developmental stages. Behav. Genet. In press.Google Scholar
  11. Dudbridge F. (2003). Pedigree disequilibrium tests for multilocus haplotypes. Genet. Epidemiol. 25:115–121PubMedCrossRefGoogle Scholar
  12. Edenberg H. J., Dick D. M., Xuei X., Tian H., Almasy L., Bauer L. O., Crowe R. R., Goate A., Hesselbrock V., Jones K., Kwon J., Li T. K., Nurnberger J. I., Jr., O’Connor S. J., Reich T., Rice J., Schuckit M. A., Porjesz B., Foroud T., and Begleiter H. (2004). Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. Am. J. Hum. Genet. 74:705–714PubMedCrossRefGoogle Scholar
  13. Fehr C., Sander T., Tadic A., Lenzen K. P., Anghelescu I., Klawe C., Dahmen N., Schmidt L. G., and Szegedi A. (2006). Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis. Psychiatry Genet. 16:9–17CrossRefGoogle Scholar
  14. Ferraro L., Tomasini M. C., Cassano T., Bebe B. W., Siniscalchi A., O’Connor,W. T., Magee P., Tanganelli S., Cuomo V., and Antonelli T. (2001a). Cannabinoid receptor agonist WIN 55,212-2 inhibits rat cortical dialysate gamma-aminobutyric acid levels. J. Neurosci. Res. 66:298–302CrossRefGoogle Scholar
  15. Ferraro L., Tomasini M. C., Gessa G. L., Bebe B. W., Tanganelli S., and Antonelli T. (2001b). The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. Cereb. Cortex 11:728–733CrossRefGoogle Scholar
  16. Foroud T., Edenberg H. J., Goate A., Rice J., Flury L., Koller D. L., Bierut L. J., Conneally P. M., Nurnberger J. I., Bucholz K. K., Li T. K., Hesselbrock V., Crowe R., Schuckit M., Porjesz B., Begleiter H., and Reich T. (2000). Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping. Alcohol Clin. Exp. Res. 24:933–945PubMedCrossRefGoogle Scholar
  17. Heath A. C., Bucholz K. K., Madden P. A., Dinwiddie S. H., Slutske W. S., Bierut L. J., Statham D. J., Dunne M. P., Whitfield J. B., and Martin N. G. (1997). Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychol. Med. 27:1381–1396PubMedCrossRefGoogle Scholar
  18. Hesselbrock M., Easton C., Bucholz K. K., Schuckit M., and Hesselbrock V. (1999). A validity study of the SSAGA – a comparison with the SCAN. Addiction 94:1361–1370PubMedCrossRefGoogle Scholar
  19. Jang K. L., Livesley W. J. and Vernon P. A. (1995). Alcohol and drug problems: a multivariate behavioural genetic analysis of co-morbidity. Addiction 90:1213–1221PubMedCrossRefGoogle Scholar
  20. Kandel D. and Yamaguchi K. (1993). From beer to crack: developmental patterns of drug involvement. Am. J. Public Health 83:851–855PubMedCrossRefGoogle Scholar
  21. Karkowski L. M., Prescott C. A., and Kendler K. S. (2000). Multivariate assessment of factors influencing illicit substance use in twins from female–female pairs. Am. J. Med. Genet. 96:665–670PubMedCrossRefGoogle Scholar
  22. Kaupmann K., Huggel K., Heid J., Flor P. J., Bischoff S., Mickel S. J., McMaster G., Angst C., Bittiger H., Froestl W., and Bettler B. (1997). Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature 386:239–246CrossRefGoogle Scholar
  23. Kendler K. S., Jacobson K. C., Prescott C. A., and Neale M. C. (2003a). Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am. J. Psychiatry 160:687–695CrossRefGoogle Scholar
  24. Kendler K. S., Jacobson K. C., Prescott C. A., and Neale M. C. (2003b). Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am. J. Psychiatry 160:687–695CrossRefGoogle Scholar
  25. Kendler K. S., Karkowski L., and Prescott C. A. (1999a). Hallucinogen, opiate, sedative and stimulant use and abuse in a population-based sample of female twins. Acta Psychiatry Scand. 99:368–376CrossRefGoogle Scholar
  26. Kendler K. S., Karkowski L. M., Corey L. A., Prescott C. A., and Neale M. C. (1999b). Genetic and environmental risk factors in the aetiology of illicit drug initiation and subsequent misuse in women. Br. J. Psychiatry 175:351–356Google Scholar
  27. Kendler K. S., Karkowski L. M., Neale M. C., and Prescott C. A. (2000). Illicit psychoactive substance use, heavy use, abuse, and dependence in a US population-based sample of male twins. Arch. Gen. Psychiatry 57:261–269PubMedCrossRefGoogle Scholar
  28. Kendler K. S. and Prescott C. A. (1998b). Cocaine use, abuse and dependence in a population-based sample of female twins. Br. J. Psychiatry 173:345–350Google Scholar
  29. Kendler K. S. and Prescott C. A. (1998a). Cannabis use, abuse, and dependence in a population-based sample of female twins. Am. J. Psychiatry 155:1016–1022Google Scholar
  30. Kendler K. S., Prescott C. A., Myers J., and Neale M. C. (2003c). The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch. Gen. Psychiatry 60:929–937CrossRefGoogle Scholar
  31. Lappalainen J., Krupitsky E., Remizov M., Pchelina S., Taraskina A., Zvartau E., Somberg L. K., Covault J., Kranzler H. R., Krystal J. H., and Gelernter J. (2005). Association between alcoholism and gamma-amino butyric acid alpha2 receptor subtype in a Russian population. Alcohol Clin. Exp. Res. 29:493–498PubMedCrossRefGoogle Scholar
  32. Madden, P. A., Saccone, S. F., Pergadia, M. L., Agrawal, A., Todorov, A. A., Dick, D. M., Loukola, A., Broms, U., Maunu, H., Heikkila, K., Widen, E., Montgomery, G., Peltonen, L., Kaprio, J., Martin, N. G., and Rice, J. P. (2005). Genetic vulnerability for nicotine dependence: linkage results from the NAG (Nicotine Addiction Genetics) project. Am. J. Med. Genet., Neuropsych. Genet. 138B:16.Google Scholar
  33. Maes H. H., Woodard C. E., Murrelle L., Meyer J. M., Silberg J. L., Hewitt J. K., Rutter M., Simonoff E., Pickles A., Carbonneau R., Neale M. C., and Eaves L. J. (1999). Tobacco alcohol and drug use in eight- to sixteen-year-old twins: the Virginia Twin Study of Adolescent Behavioral Development. J. Stud. Alcohol 60:293–305PubMedGoogle Scholar
  34. Martin E. R., Bass M. P., and Kaplan N. L. (2001). Correcting for a potential bias in the pedigree disequilibrium test. Am. J. Hum. Genet. 68:1065–1067PubMedCrossRefGoogle Scholar
  35. Martin E. R., Monks S. A., Warren L. L., and Kaplan N. L. (2000). A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am. J. Hum. Genet. 67:146–154PubMedCrossRefGoogle Scholar
  36. McGue M. (1999). The behavioral genetics of alcoholism. Curr. Direct. Psychol. Sci. 8:109–115CrossRefGoogle Scholar
  37. McGue M., Elkins I., and Iacono W. G. (2000). Genetic and environmental influences on adolescent substance use and abuse. Am. J. Med. Genet. 96:671–677PubMedCrossRefGoogle Scholar
  38. McGue M., Pickens R. W., and Svikis D. S. (1992). Sex and age effects on the inheritance of alcohol problems: a twin study. J. Abnorm. Psychol. 101:3–17PubMedCrossRefGoogle Scholar
  39. McGue M., Slutske W. and Iacono W. G. (1999). Personality and substance use disorders: II. Alcoholism versus drug use disorders. J. Consult. Clin. Psychol. 67:394–404PubMedCrossRefGoogle Scholar
  40. Meller W. H., Rinehart R., Cadoret R. J., and Troughton E. (1988). Specific familial transmission in substance abuse. Int. J. Addict. 23:1029–1039PubMedGoogle Scholar
  41. Merikangas K. R., Stolar M., Stevens D. E., Goulet J., Preisig M. A., Fenton B., Zhang H., O’Malley S. S. and Rounsaville B. J. (1998). Familial transmission of substance use disorders. Arch. Gen. Psychiatry 55:973–979PubMedCrossRefGoogle Scholar
  42. Miles D. R., van den Bree M. B., Gupman A. E., Newlin D. B., Glantz M. D., and Pickens R. W. (2001). A twin study on sensation seeking, risk taking behavior and marijuana use. Drug Alcohol Depend. 62:57–68PubMedCrossRefGoogle Scholar
  43. Mirin S. M., Weiss R. D., Griffin M. L., and Michael J. L. (1991). Psychopathology in drug abusers and their families. Compr. Psychiatry 32:36–51PubMedCrossRefGoogle Scholar
  44. Pickens R. W., Svikis D. S., McGue M., and LaBuda M. C. (1995). Common genetic mechanisms in alcohol, drug, and mental disorder comorbidity. Drug Alcohol Depend. 39:129–138PubMedCrossRefGoogle Scholar
  45. Porjesz B., Begleiter H., Wang K., Almasy L., Chorlian D. B., Stimus A. T., Kuperman S., O’Connor S. J., Rohrbaugh J., Bauer L. O., Edenberg H. J., Goate A., Rice J. P., and Reich T. (2002). Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes. Biol. Psychol. 61:229–248PubMedCrossRefGoogle Scholar
  46. Reich T., Edenberg H. J., Goate A., Williams J. T., Rice J. P., Van E. P., Foroud T., Hesselbrock V., Schuckit M. A., Bucholz K., Porjesz B., Li T. K., Conneally P. M., Nurnberger J. I., Jr., Tischfield J. A., Crowe R. R., Cloninger C. R., Wu W., Shears S., Carr K., Crose C., Willig C., and Begleiter H. (1998). Genome-wide search for genes affecting the risk for alcohol dependence. Am. J. Med. Genet. 81:207–215PubMedCrossRefGoogle Scholar
  47. Rhee S. H., Hewitt J. K., Young S. E., Corley R. P., Crowley T. J., and Stallings M. C. (2003). Genetic and environmental influences on substance initiation, use, and problem use in adolescents. Arch. Gen. Psychiatry 60:1256–1264PubMedCrossRefGoogle Scholar
  48. Saccone N. L., Kwon J. M., Corbett J., Goate A., Rochberg N., Edenberg H. J., Foroud T., Li T. K., Begleiter H., Reich T., and Rice J. P. (2000). A genome screen of maximum number of drinks as an alcoholism phenotype. Am. J. Med. Genet. 96:632–637PubMedCrossRefGoogle Scholar
  49. Substance Abuse and Mental Health Services Administration (SAMHSA). 2003 National Survey on Drug Use and Health, 2005.Google Scholar
  50. Tsuang M. T., Bar J. L., Harley R. M., and Lyons M. J. (2001). The Harvard Twin Study of Substance Abuse: what we have learned. Harv. Rev. Psychiatry 9:267–279PubMedCrossRefGoogle Scholar
  51. Tsuang M. T., Lyons M. J., Meyer J. M., Doyle T., Eisen S. A., Goldberg J., True W., Lin N., Toomey R., and Eaves L. (1998). Co-occurrence of abuse of different drugs in men: the role of drug- specific and shared vulnerabilities. Arch. Gen. Psychiatry 55:967–972PubMedCrossRefGoogle Scholar
  52. van den Bree M. B., Johnson E. O., Neale M. C., and Pickens R. W. (1998). Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug Alcohol Depend. 52:231–241PubMedCrossRefGoogle Scholar
  53. Wagner F. A. and Anthony J. C. (2002). Into the world of illegal drug use: exposure opportunity and other mechanisms linking the use of alcohol, tobacco, marijuana, and cocaine. Am. J. Epidemiol. 155:918–925PubMedCrossRefGoogle Scholar
  54. Williams J. T., Begleiter H., Porjesz B., Edenberg H. J., Foroud T., Reich T., Goate A., Van E. P., Almasy L., and Blangero J. (1999). Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. II. Alcoholism and event-related potentials. Am. J. Hum. Genet. 65:1148–1160PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Arpana Agrawal
    • 1
  • Howard J. Edenberg
    • 2
  • Tatiana Foroud
    • 2
  • Laura J. Bierut
    • 1
  • Gerald Dunne
    • 1
  • Anthony L. Hinrichs
    • 1
  • John I. Nurnberger
    • 2
  • Raymond Crowe
    • 3
  • Samuel Kuperman
    • 3
  • Marc A. Schuckit
    • 4
  • Henri Begleiter
    • 5
  • Bernice Porjesz
    • 5
  • Danielle M. Dick
    • 1
    • 6
  1. 1.Department of PsychiatryWashington University in St. LouisSt. LouisUSA
  2. 2.Indiana University School of MedicineIndianapolisUSA
  3. 3.University of IowaIowa CityUSA
  4. 4.University of California–San DiegoSan DiegoUSA
  5. 5.State University of New YorkNew YorkUSA
  6. 6.Department of PsychiatryWashington University in St. LouisSt. LouisUSA

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