Advertisement

Behavior Genetics

, Volume 36, Issue 4, pp 577–590 | Cite as

The Role of GABRA2 in Risk for Conduct Disorder and Alcohol and Drug Dependence across Developmental Stages

  • Danielle M. DickEmail author
  • Laura Bierut
  • Anthony Hinrichs
  • Louis Fox
  • Kathleen K. Bucholz
  • John Kramer
  • Samuel Kuperman
  • Victor Hesselbrock
  • Marc Schuckit
  • Laura Almasy
  • Jay Tischfield
  • Bernice Porjesz
  • Henri Begleiter
  • John NurnbergerJr.
  • Xiaoling Xuei
  • Howard J. Edenberg
  • Tatiana Foroud
Article

 

We use findings from the behavior genetics literature about how genetic factors (latently) influence alcohol dependence and related disorders to develop and test hypotheses about the risk associated with a specific gene, GABRA2, across different developmental stages. This gene has previously been associated with adult alcohol dependence in the Collaborative Study of the Genetics of Alcoholism (COGA) sample [Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., Crowe, R., Goate, A., Hesselbrock, V., Jones, K. A., Kwon, J., Li, T. K., Nurnberger Jr., J. I., O’Connor, S. J., Reich, T., Rice, J., Schuckit, M., Porjesz, B., Foroud, T., and Begleiter, H. (2004). Am. J. Hum. Genet74:705–714] and other studies [Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., and Kranzler, H. R. (2004). Am. J. Med. Genet. B Neuropsychiatr. Genet129B:104–109; Lappalainen, J., Krupitsky, E., Remizov, M., Pchelina, S., Taraskina, A., Zvartau, E., Somberg, L. K., Covault, J., Kranzler, H. R., Krystal, J., and Gelernter, J. (2005). Alcohol. Clin. Exp. Res29:493–498]. In a sample of children and adolescents ascertained as part of the COGA project, we find that GABRA2 is significantly associated with childhood conduct disorder symptoms, but not with childhood alcohol dependence symptoms. A consistent elevation in risk for alcohol dependence associated with GABRA2 is not evident until the mid-20s and then remains throughout adulthood. GABRA2 is also associated with other drug dependence in our sample, both in adolescence and adulthood.

Keywords

Alcohol conduct disorder dependence drug GABA substance use 

Notes

Acknowledgments

The Collaborative Study on the Genetics of Alcoholism (COGA) (Principal Investigator: H. Begleiter; Co-Principal Investigators: L. Bierut, H. Edenberg, V. Hesselbrock, B. Porjesz) includes nine different centers where data collection, analysis, and storage take place. The nine sites and Principal Investigators and Co-Investigators are: University of Connecticut (V. Hesselbrock); Indiana University (H. Edenberg, J. Nurnberger Jr., P.M. Conneally, T. Foroud); University of Iowa (S. Kuperman, R. Crowe); SUNY HSCB (B. Porjesz, H. Begleiter); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice); University of California at San Diego (M. Schuckit); Howard University (R. Taylor); Rutgers University (J. Tischfield); Southwest Foundation (L. Almasy). Zhaoxia Ren serves as the NIAAA Staff Collaborator. This national collaborative study is supported by the NIH Grant U10AA08401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

In memory of Theodore Reich, M.D., Co-Principal Investigator of COGA since its inception and one of the founders of modern psychiatric genetics, we acknowledge his immeasurable and fundamental scientific contributions to COGA and the field.

Preparation of this manuscript was also supported by AA007728 to A. Heath.

References

  1. American Psychiatric Association. (1987) Diagnostic and Statistical Manual of Mental Disorders: IIIR. American Psychiatric Association, Washington DCGoogle Scholar
  2. Bierut L., Dinwiddle S. H., Begleiter H., Crowe R., Hesselbrock V., Nurnberger Jr. J. I., Porjesz B., Schuckit M., 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. Psychiatry 55: 982–988CrossRefPubMedGoogle Scholar
  3. Boehnke, M. (1991). Allele frequency estimation from pedigree data. Am. J. Hum.Genet. 48: 22–25PubMedGoogle Scholar
  4. Bucholz K. K., Cadoret R., Cloninger C. R., Dinwiddie S. H., Hesselbrock V. M., Nurnberger J. J. I., Reich T., Schmidt I. and Schuckit M. A. (1994). A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. J. Stud. Alcohol 55: 149–158PubMedGoogle Scholar
  5. Chen L., Yang C., Mower G. D. (2001). Developmental changes in the expression of GABA(A) receptor subunits (alpha(1), alpha(2), alpha(3)) in the cat visual cortex and the effects of dark rearing. Brain Res. Mol. Brain Res. 88: 135–143CrossRefPubMedGoogle Scholar
  6. Claus E.B., Risch N.J., Thompson W.D. (1990). Using age of onset to distinguish between subforms of breast cancer. Ann. Hum. Genet. 54: 169–177PubMedCrossRefGoogle Scholar
  7. Cleves M. A., Gould W. W., Gutierrex R. C. (2004) An Introduction to Survival Analysis using Stata. Stata Corporation, College Station TXGoogle Scholar
  8. Cloninger C. R., Bohman M., Sigvardsson S. (1981). Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch. Gen. Psychiatry 38: 861–868PubMedGoogle Scholar
  9. Covault J., Gelernter J., Hesselbrock V., Nellissery M., Kranzler H. R. (2004). Allelic and haplotypic association of GABRA2 with alcohol dependence. Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B: 104–109CrossRefPubMedGoogle Scholar
  10. Dick, D. M., Agrawal, A., Schuckit, M., Bierut, L., Hinrichs, A. L., Cloninger, C. R., Fox, L., Mullaney, J., Hesselbrock, V., Nurnberger Jr., J. I., Almasy, L., Foroud, T., Porjesz, B., Edenberg, H. J., and Begleiter, H. (2005, in press). Marital status, alcohol dependence, and GABRA2: evidence for gene–environment correlation and interaction. J. Stud. Alcohol Google Scholar
  11. Dick D. M., Li T. K., Edenberg H. J., Hesselbrock V., Kramer J. R. and Foroud T. (2003). A genome-wide screen for genes influencing conduct disorder. Mol. Psychiatry 9: 81–86CrossRefGoogle Scholar
  12. Edenberg H. J., Dick D. M., Xuei X., Tian H., Almasy L., Bauer L. O., Crowe R., Goate A., Hesselbrock V., Jones K. A., Kwon J., Li T. K., Nurnberger Jr. J. I., O’Connor S. J., Reich T., Rice J., Schuckit M., Porjesz B., Foroud T., Begleiter H. (2004). Variations in GABRA2, encoding the \(\alpha2\) subunit of the GABA-A receptor are associated with alcohol dependence and with brain oscillations. Am. J. Hum. Genet. 74: 705–714CrossRefPubMedGoogle Scholar
  13. Fisher, S. L., Bucholz, K. K., Reich, W., Fox, L., Kuperman, S., Kramer, J. R., Hesselbrock, V., Dick, D. M., Nurnberger, J. I. Jr., Edenberg, H. J., and Bierut, L. (2005, under review). Teenagers are right – Parents don’t know much: an analysis of adolescent-parent agreement on reports of adolescent substance use, abuse, and dependenceGoogle Scholar
  14. Goldstein R. B., Prescott C. and Kendler K. S. (2001). Genetic and environmental factors in conduct problems and adult antisocial behavior among adult female twins. J. Nerv. Ment. Dis. 189: 201–209CrossRefPubMedGoogle Scholar
  15. Heath A. C., Bucholz K. K., Madden P. A., Dinwiddle S. H., Slutske W. S., Bierut L., 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: 1381–1396CrossRefPubMedGoogle Scholar
  16. 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: 1361–1370CrossRefPubMedGoogle Scholar
  17. Institute, S. (2001) Version 8 of the SAS System for Windows. SAS Institute Inc., Cary, NCGoogle Scholar
  18. Kendler K. S., Prescott C., Myers J. and Neale M. C. (2003). The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch. Gen. Psychiatry 60: 929–937CrossRefPubMedGoogle Scholar
  19. Knopik, V. (2005) Alcoholism and externalizing disorders: comorbidity risk mediated via intrauterine exposure. Paper presented at the Fifth Annual Guze Symposium on Alcoholism, St. Louis, MO, 2005Google Scholar
  20. Kuperman S., Schlosser S. S., Kramer J. R., Bucholz K. K., Hesselbrock V., Reich T. and Reich W. (2001a). Developmental sequence from disruptive behavior diagnosis to adolescent alcohol dependence. Am. J. Psychiatry 158: 2022–2026CrossRefGoogle Scholar
  21. Kuperman S., Schlosser S. S., Kramer J. R., Bucholz K. K., Hesselbrock V., Reich T. and Reich W. (2001b). Risk domains associated with an adolescent alcohol dependence diagnosis. Addiction 96: 629–636CrossRefGoogle Scholar
  22. Lappalainen J., Krupitsky E., Remizov M., Pchelina S., Taraskina A., Zvartau E., Somberg L. K., Covault J., Kranzler H. R., Krystal J., Gelernter J. (2005). Association between alcoholism and gamma-amino butyric acid alpha2 receptor subtype in a Russian population. Alcohol. Clin. Exp. Res. 29: 493–498CrossRefPubMedGoogle Scholar
  23. Mantel N. and Haenszel (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22: 719–748PubMedGoogle Scholar
  24. McGue M. (1999). The behavioral genetics of alcoholism. Curr. Dir. Psychol. Sci. 8: 109–115CrossRefGoogle Scholar
  25. McGue M. and Bouchard J.T.J. (1998). Genetic and environmental influences on human behavioral differences. Ann. Rev. Neurosci. 21: 1–24CrossRefPubMedGoogle Scholar
  26. McGuffin P., Riley B. and Plomin R. (2001). Toward behavioral genomics. Science 291: 1232–1249CrossRefPubMedGoogle Scholar
  27. Molina B. S. G., Bukstein O. G. and Lynch K. G. (2002). Attention-deficit/hyperactivity disorder and conduct disorder symptomatology in adolescents with alcohol use disorder. Psychol. Addict. Behav. 16: 161–164CrossRefPubMedGoogle Scholar
  28. Moss H. B., Lynch K. G. (2001). Comorbid disruptive behavior disorder symptoms and their relationship to adolescent alcohol use disorders. Drug Alcohol Depend. 64: 75–83CrossRefPubMedGoogle Scholar
  29. Reich T. (1996). A genomic survey of alcohol dependence and related phenotypes: results from the Collaborative Study on the Genetics of Alcoholism (COGA). Alcohol. Clin. Exp. Res. 20: 133-137PubMedCrossRefGoogle Scholar
  30. 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: 1256–1264CrossRefPubMedGoogle Scholar
  31. Rose R.J. (1995). Genes and human behavior. Ann. Rev. Psychol. 46: 625–654CrossRefGoogle Scholar
  32. Rose R. J., Dick D. M., Viken R. J. and Kaprio J. (2001a). Gene–environment interaction in patterns of adolescent drinking: regional residency moderates longitudinal influences on alcohol use. Alcohol. Clin. Exp. Res. 25: 637–643CrossRefGoogle Scholar
  33. Rose R. J., Dick D. M., Viken R. J., Pulkkinen L. and Kaprio J. (2001b). Drinking or abstaining at age 14: a genetic epidemiological study. Alcohol. Clin. Exp. Res. 25: 1594–1604CrossRefGoogle Scholar
  34. Rose R. J., Dick D. M., Viken R. J., Pulkkinen L., Nurnberger Jr. J. I. and Kaprio J. (2004). Genetic and environmental effects on conduct disorder, alcohol dependence symptoms, and their covariation at age 14. Alcohol. Clin. Exp. Res. 28: 1541–1548CrossRefPubMedGoogle Scholar
  35. Rose R. J., Viken R. J., Dick D. M., Bates J., Pulkkinen L. and Kaprio J. (2003). It does take a village: nonfamilial environments and children’s behavior. Psychol. Sci. 14: 273–277CrossRefPubMedGoogle Scholar
  36. Simonoff E., Pickles A., Meyer J.M., Silberg J.L. and Maes H. H. (1998). Genetic and environmental influences on subtypes of conduct disorder behavior in boys. J. Abnorm. Child Psychol. 26: 495–509PubMedGoogle Scholar
  37. Slutske W. S., Heath A. C., Dinwiddie S. H., Madden P. A. F., Bucholz K. K., Dunne M. P., Statham D. J. and Martin N. G. (1997). Modeling genetic and environmental influences in the etiology of conduct disorder: a study of 2682 adult twin pairs. J. Abnorm. Psychol. 106: 266–279CrossRefPubMedGoogle Scholar
  38. Slutske W. S., Heath A. C., Dinwiddle S. H., Madden P. A. F., Bucholz K. K., Dunne M. P., Statham D. J. and Martin N. G. (1998). Common genetic risk factors for conduct disorder and alcohol dependence. J. Abnorm. Psychol. 107: 363–374CrossRefPubMedGoogle Scholar
  39. StataCorp (2003) Stata Statistical Software: Release 80. Stata Corporation, College Station, TXGoogle Scholar
  40. White H. R., Zie M., Thompson W., Loeber R. and Stouthamer-Loeber M. (2001). Psychopathology as a predictor of adolescent drug use trajectories. Psychol. Addict. Behav. 15: 210–218CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Danielle M. Dick
    • 1
    • 9
    Email author
  • Laura Bierut
    • 1
  • Anthony Hinrichs
    • 1
  • Louis Fox
    • 1
  • Kathleen K. Bucholz
    • 1
  • John Kramer
    • 2
  • Samuel Kuperman
    • 2
  • Victor Hesselbrock
    • 3
  • Marc Schuckit
    • 4
  • Laura Almasy
    • 5
  • Jay Tischfield
    • 6
  • Bernice Porjesz
    • 7
  • Henri Begleiter
    • 7
  • John NurnbergerJr.
    • 8
  • Xiaoling Xuei
    • 8
  • Howard J. Edenberg
    • 8
  • Tatiana Foroud
    • 8
  1. 1.Department of Psychiatry and PsychologyWashington University School of MedicineSt. LouisUSA
  2. 2.University of Iowa School of MedicineIowa CityUSA
  3. 3.University of Connecticut School of MedicineFarmingtonUSA
  4. 4.University of California at San Diego School of MedicineLa JollaUSA
  5. 5.Southwest FoundationSan AntonioUSA
  6. 6.Rutgers UniversityPiscatawayUSA
  7. 7.SUNY Health Science Center at BrooklynBrooklynUSA
  8. 8.Indiana University School of MedicineIndianapolisUSA
  9. 9.WUSM PsychiatrySt. LouisUSA

Personalised recommendations