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Behavior Genetics

, Volume 43, Issue 5, pp 402–414 | Cite as

Gender-Specific Gene–Environment Interaction in Alcohol Dependence: The Impact of Daily Life Events and GABRA2

  • Brea L. PerryEmail author
  • Bernice A. Pescosolido
  • Kathleen Bucholz
  • Howard Edenberg
  • John Kramer
  • Samuel Kuperman
  • Marc Alan Schuckit
  • John I. NurnbergerJr.
Original Research

Abstract

Gender-moderated gene–environment interactions are rarely explored, raising concerns about inaccurate specification of etiological models and inferential errors. The current study examined the influence of gender, negative and positive daily life events, and GABRA2 genotype (SNP rs279871) on alcohol dependence, testing two- and three-way interactions between these variables using multi-level regression models fit to data from 2,281 White participants in the Collaborative Study on the Genetics of Alcoholism. Significant direct effects of variables of interest were identified, as well as gender-specific moderation of genetic risk on this SNP by social experiences. Higher levels of positive life events were protective for men with the high-risk genotype, but not among men with the low-risk genotype or women, regardless of genotype. Our findings support the disinhibition theory of alcohol dependence, suggesting that gender differences in social norms, constraints and opportunities, and behavioral undercontrol may explain men and women’s distinct patterns of association.

Keywords

Gender Genetics Gene–environment interaction Daily hassles and uplifts Alcohol dependence 

Notes

Acknowledgment

This research was funded in part by a grant from the Peter F. McManus Charitable Trust. The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut, includes ten different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, A. Goate, J. Rice, K. Bucholz); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield); Southwest Foundation (L. Almasy), Howard University (R. Taylor) and Virginia Commonwealth University (D. Dick). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. This national collaborative study is supported by NIH Grant U10 AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Funding support for GWAS genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Institute on Alcohol Abuse and Alcoholism, the NIH GEI (U01HG004438), and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). The authors thank Kim Doheny and Elizabeth Pugh from CIDR and Justin Paschall from the NCBI dbGaP staff for valuable assistance with genotyping and quality control in developing the dataset available at dbGaP.

Supplementary material

10519_2013_9607_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 kb)

References

  1. Agrawal A, Edenberg HJ, Foroud T, Bierut LJ, Dunne G, Hinrichs AL, Nurnberger JI, Crowe R, Kuperman S, Schuckit MA, Begleiter H, Porjesz B, Dick DM (2006) Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample. Behav Genet 36:640–650PubMedCrossRefGoogle Scholar
  2. Allison P (1999) Comparing logit and probit coefficients across groups. Sociol Methods Res 28:186–208CrossRefGoogle Scholar
  3. Bancroft A (2009) Drugs intoxication and society. Polity, CambridgeGoogle Scholar
  4. Bearman PS, Brückner H (2002) Opposite-sex twins and adolescent same-sex attraction. Am J Sociol 107:1179–1205CrossRefGoogle Scholar
  5. Begleiter H, Porjesz B (1999) What is inherited in the predisposition toward alcoholism? A proposed model. Alcoholism 23:1125–1135PubMedGoogle Scholar
  6. Bird CE, Rieker PP (2008) Gender and health: the effects of contrained choices and social policies. Cambridge University Press, New YorkCrossRefGoogle Scholar
  7. Brambor T, Clark WR, Golder M (2006) Understanding interaction models: improving empirical analyses. Polit Anal 14:63–82CrossRefGoogle Scholar
  8. Brookes ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ (2004) Subgroup analyses in randomized trials: risks of subgroup-specific analyses: power and sample size for the interaction test. J Clin Epidemiol 57:229–236PubMedCrossRefGoogle Scholar
  9. Caspi A, Moffitt TE, Newman DL, Silva PA (1996) Behavioral observations at age 3 years predict adult psychiatric disorders: longitudinal evidence from a birth cohort. Arch Gen Psychiatry 53:1033–1039PubMedCrossRefGoogle Scholar
  10. Caspi A, Harrington H, Moffitt TE, Begg D, Dickson N, Langley J, Silva PA (1997) Personality differences predict health-risk behaviors in young adulthood: evidence from a longitudinal study. J Pers Soc Psychol 73:1052–1063PubMedCrossRefGoogle Scholar
  11. Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE (2010) Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167(5):509PubMedCrossRefGoogle Scholar
  12. Covault J, Gelernter J et al (2007) Markers in the 5′-region of GABRG1 associate to alcohol dependence and are in linkage disequilibrium with markers in the adjacent GABRA2 gene. Neuropsychopharmacology 33(4):837–848PubMedCrossRefGoogle Scholar
  13. Cross CP, Copping LT, Campbell A (2011) Sex differences in impulsivity: a meta-analysis. Psychol Bull 137:97–130PubMedCrossRefGoogle Scholar
  14. DeLongis A, Coyne JC, Dakof G, Folkman S, Lazarus RS (1982) Relationship of daily hassles, uplifts, and major life events to health status. Health Psychol 1:119–136CrossRefGoogle Scholar
  15. Dick DM, Rose RJ, Viken RJ, Kaprio J, Koskenvuo M (2001) Exploring gene–environment interactions: socioregional moderation of alcohol use. J Abnorm Psychol 110:625–632PubMedCrossRefGoogle Scholar
  16. Dick D, Bierut L, Hinrichs A, Fox L, Bucholz K, Kramer J, Kuperman S, Hesselbrock V, Schuckit M, Almasy L, Tischfield J, Porjesz B, Begleiter H, Nurnberger J, Xuei X, Edenberg H, Foroud T (2006a) The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages. Behav Genet 36:577–590PubMedCrossRefGoogle Scholar
  17. Dick DM, Agrawal A, Schuckit MA, Bierut L, Hinrichs A, Fox L, Mullaney J, Cloninger CR, Hesselbrock V, Nurnberger JI, Almasy L, Foroud T, Porjesz B, Edenberg H, Begleiter H (2006b) Marital status, alcohol dependence, and GABRA2: evidence for gene–environment correlation and interaction. J Stud Alcohol 67:185–194PubMedGoogle Scholar
  18. Dick DM, Latendresse SJ, Lansford JE, Budde JP, Goate A, Dodge KA, Pettit GS, Bates JE (2009) Role of GABRA2 in trajectories of externalizing behavior across development and evidence of moderation by parental monitoring. Arch Gen Psychiatry 66:649–657PubMedCrossRefGoogle Scholar
  19. Dick DM, Smith G, Olausson P, Mitchell SH, Leeman RF, O’Malley SS, Sher K (2010) Review: understanding the construct of impulsivity and its relationship to alcohol use disorders. Addict Biol 15:217–226PubMedCrossRefGoogle Scholar
  20. Dick DM, Aliev F, Latendresse S, Porjesz B, Schuckit M, Rangaswamy M, Hesselbrock V, Edenberg H, Nurnberger J, Agrawal A, Bierut L, Wang J, Bucholz K, Kuperman S, Kramer J (2013) How phenotype and developmental stage affect the genes we find: GABRA2 and impulsivity. Twin Res Hum Genet 16:661–669PubMedCrossRefGoogle Scholar
  21. Drgon T, D’Addario C et al (2006) Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions. Am J Med Genet B 141(8):854–860CrossRefGoogle Scholar
  22. Duncan LE, Keller MC (2011) A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am J Psychiatry 168(10):1041PubMedCrossRefGoogle Scholar
  23. Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO, Crowe RR, Goate A, Hesselbrock V, Jones K, Kwon J, Li T-K, Nurnberger JI Jr, O’Connor SJ, Reich T, Rice J, Schuckit MA, Porjesz B, Foroud T, Begleiter H (2004) Variations in GABRA2, encoding the [alpha]2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet 74:705–714PubMedCrossRefGoogle Scholar
  24. Eitle D, Taylor J, Eitle TM (2010) Heavy episodic alcohol use in emerging adulthood: the role of early risk factors and young adult social roles. J Drug Issues 40:295–320CrossRefGoogle Scholar
  25. Enoch M-A (2008) The role of GABAA receptors in the development of alcoholism. Pharmacol Biochem Behav 90(1):95PubMedCrossRefGoogle Scholar
  26. Enoch M-A, Schwartz L, Albaugh B, Virkkunen M, Goldman D (2006) Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism. Am J Med Genet B 141B:599–607CrossRefGoogle Scholar
  27. Enoch M-A, Hodgkinson CA, Yuan Q, Shen P-H, Goldman D, Roy A (2010) The influence of GABRA2, childhood trauma, and their interaction on alcohol, heroin, and cocaine dependence. Biol Psychiatry 67:20–27PubMedCrossRefGoogle Scholar
  28. Fillmore KM (1987) Women's drinking across the adult life course as compared to men's. Brit J Addict 82(7):801–811Google Scholar
  29. Fitzmaurice G, Laird N, Ware J (2004) Applied longitudinal analysis. Wiley, New YorkGoogle Scholar
  30. Gelernter J, Kranzler HR et al (2009) Dense genomewide linkage scan for alcohol dependence in African Americans: significant linkage on chromosome 10. Biol Psychiatry 65(2):111–115PubMedCrossRefGoogle Scholar
  31. Gomberg ESL (1997) Alcohol abuse: age and gender differences. In: Wilsnack RW, Wilsnack SC (eds) Gender and alcohol: individual and social perspectives. Rutgers Center of Alcohol Studies, New Brunswick, pp 225–244Google Scholar
  32. Grant BF (1997) Prevalence and correlates of alcohol use and DSM-IV alcohol dependence in the United States: results of the National Longitudinal Alcohol Epidemiologic Survey. J Stud Alcohol 58:464–473PubMedGoogle Scholar
  33. Guo G (2006) The linking of sociology and biology. Soc Forces 85:145–150CrossRefGoogle Scholar
  34. Harrison PJ, Tunbridge EM (2007) Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33:3037–3045PubMedCrossRefGoogle Scholar
  35. Heath AC, Nelson EC (2002) Effects of the interaction between genotype and environment. Research into the genetic epidemiology of alcohol dependence. Alcohol Res Health 26:193–201PubMedGoogle Scholar
  36. Hesselbrock M, Easton C, Bucholz KK, Schuckit M, Hesselbrock V (1999) A validity study of the SSAGA-a comparison with the SCAN. Addiction 94:1361–1370PubMedCrossRefGoogle Scholar
  37. Horwitz AV, White HR (1987) Gender role orientations and styles of pathology among adolescents. J Health Soc Behav 28:158–170PubMedCrossRefGoogle Scholar
  38. Huselid RF, Cooper ML (1992) Gender roles as mediators of sex differences in adolescent alcohol use and abuse. J Health Soc Behav 33:348–362PubMedCrossRefGoogle Scholar
  39. Keefe K (1994) Perceptions of normative social pressure and attitudes toward alcohol use: changes during adolescence. J Stud Alcohol 55:46–54PubMedGoogle Scholar
  40. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 51:8–19PubMedCrossRefGoogle Scholar
  41. Keyes KM, Grant BF, Hasin DS (2008) Evidence for a closing gender gap in alcohol use, abuse, and dependence in the United States population. Drug Alcohol Depend 93:21–29PubMedCrossRefGoogle Scholar
  42. Koopmans JR, Slutske WS, van Baal GCM, Boomsma DI (1999) The influence of religion on alcohol use initiation: evidence for genotype X environment interaction. Behav Genet 29:445–453PubMedCrossRefGoogle Scholar
  43. Kreek MJ, Nielsen DA, Butelman ER, LaForge KS (2005) Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 8:1450–1457PubMedCrossRefGoogle Scholar
  44. Landrine H, Bardwell S, Dean T (1988) Gender expectations for alcohol use: a study of the significance of the masculine role. Sex Roles 19:703–712CrossRefGoogle Scholar
  45. Lewis MA, Neighbors C (2004) Gender-specific misperceptions of college student drinking norms. Psychol Addict Behav 18:334–339PubMedCrossRefGoogle Scholar
  46. Long JS (2009) Group comparisons in logit and probit using predicted probabilities. Indiana University, pp 1–25Google Scholar
  47. Loscocco K, Spitze G (2007) Gender patterns in provider role attitudes and behavior. J Fam Issues 28(7):934–954Google Scholar
  48. Luan J, Wong M et al (2001) Sample size determination for studies of gene–environment interaction. Int J Epidemiol 30(5):1035–1040PubMedCrossRefGoogle Scholar
  49. Martino SC, Collins RL, Ellickson PL (2004) Substance use and vulnerability to sexual and physical aggression: a longitudinal study of young adults. Violence vict 19(5):521–540Google Scholar
  50. Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154PubMedCrossRefGoogle Scholar
  51. Moffitt TE, Caspi A, Rutter M (2006) Measured gene–environment interactions in psychopathology. Perspect Psychol Sci 1:5–27CrossRefGoogle Scholar
  52. Nilsson KW, Sjöberg RL, Damberg M, Alm PO, Öhrvik J, Leppert J, Lindström L, Oreland L (2005) Role of the serotonin transporter gene and family function in adolescent alcohol consumption. Alcoholism 29:564–570PubMedGoogle Scholar
  53. Nolen-Hoeksema S, Hilt L (2006) Possible contributors to the gender differences in alcohol use and problems. J Gen Psychol 133:357–374PubMedCrossRefGoogle Scholar
  54. Nurnberger JI Jr, Wiegand R, Bucholz K, O’Connor S, Meyer ET, Reich T, Rice J, Schuckit M, King L, Petti T, Bierut L, Hinrichs AL, Kuperman S, Hesselbrock V, Porjesz B (2004) A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands. Arch Gen Psychiatry 61:1246–1256PubMedCrossRefGoogle Scholar
  55. Ober C, Loisel DA, Gilad Y (2008) Sex-specific genetic architecture of human disease. Nat Rev Genet 9:911–922PubMedCrossRefGoogle Scholar
  56. Ono H, Shirakawa O, Nushida H, Ueno Y, Maeda K (2004) Association between catechol-O-methyltransferase functional polymorphism and male suicide completers. Neuropsychopharmacology 29:1374–1377PubMedCrossRefGoogle Scholar
  57. Patsopoulos NA, Tatsioni A, Ioannidis JPA (2007) Claims of sex differences. J Am Med Assoc 298:880–893CrossRefGoogle Scholar
  58. Pescosolido BA, Perry BL, Long JS, Martin JK, Nurnberger JI Jr, Hesselbrock V (2008) Under the influence of genetics: how transdisciplinarity leads us to rethink social pathways to illness. Am J Sociol 114:S171–S201PubMedCrossRefGoogle Scholar
  59. Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A (2008) The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B 147B:543–549CrossRefGoogle Scholar
  60. Philibert RA, Gunter TD, Beach SRH, Brody GH, Hollenbeck N, Andersen A, Adams W (2009) Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies. Psychiatr Genet 19:91–98. doi: 10.1097/YPG.1090b1013e3283208026 PubMedCrossRefGoogle Scholar
  61. Porjesz B, Rangaswamy M (2007) Neurophysiological endophenotypes, CNS disinhibition, and risk for alcohol dependence and related disorders. ScientificWorldJournal 7:131–141PubMedCrossRefGoogle Scholar
  62. Rabe-Hesketh S, Skrondal A (2008) Multilevel and longitudinal modeling using stata. Stata, College StationGoogle Scholar
  63. Reich T (1996) A genomic survey of alcohol dependence and related phenotypes: results from the Collaborative Study on the Genetics of Alcoholism (COGA). Alcoholism 20:133a–137aPubMedGoogle Scholar
  64. Ricciardelli LA, Connor JP, Williams RJ, Young RM (2001) Gender stereotypes and drinking cognitions as indicators of moderate and high risk drinking among young women and men. Drug Alcohol Depend 61:129–136PubMedCrossRefGoogle Scholar
  65. Rose RJ, Dick DM, Viken RJ, Kaprio J (2001) Gene–environment interaction in patterns of adolescent drinking: regional residency moderates longitudinal influences on alcohol use. Alcoholism 25:637–643PubMedGoogle Scholar
  66. Rutledge PC, Sher KJ (2001) Heavy drinking from the freshman year into early young adulthood: the roles of stress, tension-reduction drinking motives, gender and personality. J Stud Alcohol 62:457–466PubMedGoogle Scholar
  67. Rutter M, Moffitt TE, Caspi A (2006) Gene–environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiatry 47:226–261PubMedCrossRefGoogle Scholar
  68. Schmidt C, Klee L, Ames G (1990) Review and analysis of literature on indicators of women’s drinking problems. Br J Addict 85:179–192PubMedCrossRefGoogle Scholar
  69. Schulte MT, Ramo D, Brown SA (2009) Gender differences in factors influencing alcohol use and drinking progression among adolescents. Clin Psychol Rev 29:535–547PubMedCrossRefGoogle Scholar
  70. Shanahan MJ, Hofer SM (2005) Social context in gene–environment interactions: retrospect and prospect. J Gerontol B 60:65–76CrossRefGoogle Scholar
  71. Shanahan Michael J, Vaisey S, Erickson Lance D, Smolen A (2008) Environmental contingencies and genetic propensities: social capital, educational continuation, and dopamine receptor gene DRD2. Am J Sociol 114:S260–S286PubMedCrossRefGoogle Scholar
  72. Sher KJ, Grekin ER, Williams NA (2005) The development of alcohol use disorders. Annu Rev Clin Psychol 1:493–523PubMedCrossRefGoogle Scholar
  73. Simon RW (1992) Parental role strains, salience of parental identity and gender differences in psychological distress. J Health Soc Behav 33(1):25–35Google Scholar
  74. Simon RW (1995) Gender, multiple roles, role meaning, and mental health. J Health Soc Behav 36(2):182–194Google Scholar
  75. Singer BH, Ryff CD (2001) New horizons in health: an Integrative approach. National Academy Press, WashingtonGoogle Scholar
  76. StataCorp (2011) Stata Statistical Software: Release 12. StataCorp LP, College StationGoogle Scholar
  77. Stein MB, Fallin MD, Schork NJ, Gelernter J (2005) COMT polymorphisms and anxiety-related personality traits. Neuropsychopharmacology 30:2092–2102PubMedCrossRefGoogle Scholar
  78. Umberson D, Crosnoe R, Reczek C (2010) Social relationships and health behavior across life course. Annu Rev Sociol 36:139–157PubMedCrossRefGoogle Scholar
  79. Villafuerte S, Heitzeg MM, et al (2012) Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism. Mol Psychiatry 17(5):511–519Google Scholar
  80. Villafuerte S, Strumba V, Stoltenberg SF, Zucker RA, Burmeister M (2013) Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems. Genes Brain Behav 12:525–531PubMedCrossRefGoogle Scholar
  81. Waldman ID, Robinson BF, Rhee SH (1999) A logistic regression extension of the transmission disequilibrium test for continuous traits: application to linkage disequilibrium between alcoholism and the candidate genes DRD2 and ADH3. Genet Epidemiol 17(Suppl 1):S379–S384PubMedGoogle Scholar
  82. Young-Wolff KC, Enoch MA, et al (2011) The influence of gene–environment interactions on alcohol consumption and alcohol use disorders: a comprehensive review. Clin Psychol Rev 31(5):800–816Google Scholar
  83. Zucker RA, Heitzeg MM, Nigg JT (2011) Parsing the undercontrol–disinhibition pathway to substance use disorders: a multilevel developmental problem. Child Dev Perspect 5:248–255PubMedCrossRefGoogle Scholar
  84. Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: common bisocial factors. J Pers 68:999–1029PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Brea L. Perry
    • 1
    Email author
  • Bernice A. Pescosolido
    • 2
  • Kathleen Bucholz
    • 3
  • Howard Edenberg
    • 4
  • John Kramer
    • 5
  • Samuel Kuperman
    • 5
  • Marc Alan Schuckit
    • 6
  • John I. NurnbergerJr.
    • 4
  1. 1.Department of SociologyUniversity of KentuckyLexingtonUSA
  2. 2.Department of SociologyIndiana UniversityBloomingtonUSA
  3. 3.Department of PsychiatryWashington University in St. LouisSt. LouisUSA
  4. 4.Department of Biochemistry and Molecular BiologyIndiana University School of MedicineIndianapolisUSA
  5. 5.Department of PsychiatryUniversity of Iowa College of MedicineIowa CityUSA
  6. 6.Department of PsychiatryUniversity of CaliforniaSan DiegoUSA

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