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. Genet. 74:705–714] and other studies [Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., and Kranzler, H. R. (2004). Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B: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. Res. 29:493–498]. 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.
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Notes
Although this p-value is not statistically significant at p<0.05, there is a considerably smaller number of subjects (N=532, see Table I) used in this analysis.
Although this p-value approaches significance, it appears to be due to the large number of subjects available for this analysis (N=2593, Table I).
References
American Psychiatric Association. (1987) Diagnostic and Statistical Manual of Mental Disorders: IIIR. American Psychiatric Association, Washington DC
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: 982–988
Boehnke, M. (1991). Allele frequency estimation from pedigree data. Am. J. Hum.Genet. 48: 22–25
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: 149–158
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: 135–143
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: 169–177
Cleves M. A., Gould W. W., Gutierrex R. C. (2004) An Introduction to Survival Analysis using Stata. Stata Corporation, College Station TX
Cloninger C. R., Bohman M., Sigvardsson S. (1981). Inheritance of alcohol abuse: cross-fostering analysis of adopted men. Arch. Gen. Psychiatry 38: 861–868
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: 104–109
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
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: 81–86
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: 705–714
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 dependence
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: 201–209
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: 1381–1396
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: 1361–1370
Institute, S. (2001) Version 8 of the SAS System for Windows. SAS Institute Inc., Cary, NC
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: 929–937
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, 2005
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: 2022–2026
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: 629–636
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: 493–498
Mantel N. and Haenszel (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22: 719–748
McGue M. (1999). The behavioral genetics of alcoholism. Curr. Dir. Psychol. Sci. 8: 109–115
McGue M. and Bouchard J.T.J. (1998). Genetic and environmental influences on human behavioral differences. Ann. Rev. Neurosci. 21: 1–24
McGuffin P., Riley B. and Plomin R. (2001). Toward behavioral genomics. Science 291: 1232–1249
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: 161–164
Moss H. B., Lynch K. G. (2001). Comorbid disruptive behavior disorder symptoms and their relationship to adolescent alcohol use disorders. Drug Alcohol Depend. 64: 75–83
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: 133-137
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: 1256–1264
Rose R.J. (1995). Genes and human behavior. Ann. Rev. Psychol. 46: 625–654
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: 637–643
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: 1594–1604
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: 1541–1548
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: 273–277
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: 495–509
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: 266–279
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: 363–374
StataCorp (2003) Stata Statistical Software: Release 80. Stata Corporation, College Station, TX
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: 210–218
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.
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Dick, D.M., Bierut, L., Hinrichs, A. et al. The Role of GABRA2 in Risk for Conduct Disorder and Alcohol and Drug Dependence across Developmental Stages. Behav Genet 36, 577–590 (2006). https://doi.org/10.1007/s10519-005-9041-8
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DOI: https://doi.org/10.1007/s10519-005-9041-8