Hostname: page-component-745bb68f8f-g4j75 Total loading time: 0 Render date: 2025-01-11T22:21:26.253Z Has data issue: false hasContentIssue false
  • English
  • Français

Mendelian randomization: A novel test of the gateway hypothesis and models of gene–environment interplay

Published online by Cambridge University Press:  11 October 2007

Daniel E. Irons ,
Matt McGue ,
William G. Iacono  and
William S. Oetting
Daniel E. Irons*
Affiliation:
University of Minnesota
Matt McGue
Affiliation:
University of Minnesota
William G. Iacono
Affiliation:
University of Minnesota
William S. Oetting
Affiliation:
University of Minnesota
*
Address correspondence and reprint requests to: Daniel Irons, Department of Psychology, University of Minnesota, 75 East River Road, Minneapolis, MN 55455; E-mail: [email protected].
Get access Rights & Permissions [Opens in a new window]

Abstract

To determine if drinking behavior in adolescence provides a “gateway” leading to the misuse of other psychoactive substances and antisocial behavior, we genotyped 180 Asian adolescent adoptees to determine if they inherited the deficient from of the aldehyde dehydrogenase 2 (ALDH2) enzyme that is important in the metabolism of alcohol. Based on the gateway model, we hypothesized that those with normal enzyme activity (70% of the sample) who began to misuse alcohol would also misuse other drugs and display antisocial tendencies. Those with the enzyme deficiency (30%), because they experience unpleasant side effects associated with drinking, were expected to show less evidence of alcohol misuse and thus be less likely to progress to the misuse of other substances or engage in antisocial acts. Consistent with previous research, we found that ALDH2 deficiency was significantly associated with lower rates of drinking and getting drunk but not with ever having tried alcohol. Contrary to the gateway model, we found no evidence that ALDH2 deficiency was associated with lower rates of nonalcohol substance use or antisociality. Finally, in an examination of factors that may moderate the impact of the metabolic protection because of ALDH2 deficiency, we identified siblings rather than parents as the major source of familial environmental effect on adolescent drinking.

Type
Research Article
Information
Development and Psychopathology , Volume 19 , Issue 4 , Fall 2007 , pp. 1181 - 1195
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bachman, R., & Peralta, R. (2002). The relationship between drinking and violence in an adolescent population: Does gender matter? Deviant Behavior: An Interdisciplinary Journal, 23, 1–19.CrossRefGoogle Scholar
Barnes, G. M. (1990). Impact of the family on adolescent drinking patterns. In Collins, R. L., Leonard, K. E., & Searles, J. S. (Eds.), Alcohol and the family: Research and clinical perspectives (pp. 137–161). New York: Guilford Press.Google Scholar
Brener, N. D., & Collins, J. L. (1998). Co-occurrence of health-risk behaviors among adolescents in the United States. Journal of Adolescent Health, 22, 209–213.CrossRefGoogle ScholarPubMed
Brennan, P. (2004). Commentary: Mendelian randomization and gene–environment interaction. International Journal of Epidemiology, 33, 17–21.CrossRefGoogle ScholarPubMed
Brien, J. F., & Loomis, C. W. (1983). Pharmacology of acetaldehyde. Canadian Journal of Physiology and Pharmacology, 61, 1–22.CrossRefGoogle ScholarPubMed
Cloninger, C. R., Bohman, M., & Sigvardsson, S. (1981). Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. Archives of General Psychiatry, 38, 861–868.CrossRefGoogle ScholarPubMed
Curtis, W. J., & Cicchetti, D. (2003). Moving research on resilience into the 21st century: Theoretical and methodological considerations in examining the biological contributors to resilience. Development and Psychopathology, 15, 773–810.CrossRefGoogle ScholarPubMed
Davey Smith, G., & Ebrahim, S. (2005). What can Mendelian randomisation tell us about modifiable behavioural and environmental exposures? British Medical Journal, 330, 1076–1079.CrossRefGoogle ScholarPubMed
Faden, V. B. (2006). Trends in initiation of alcohol use in the united states 1975 to 2003. Alcoholism-Clinical and Experimental Research, 30, 1011–1022.CrossRefGoogle ScholarPubMed
Gibson, H. B. (1967). Self-reported delinquency among schoolboys, and their attitudes to the police. British Journal of Social and Clinical Psychology, 6, 168–173.CrossRefGoogle Scholar
Goedde, H. W., Agarwal, D. P., Fritze, G., Meier-Tackmann, D., Singh, S., Beckmann, G., et al. (1992). Distribution of ADH2 and ALDH2 genotypes in different populations. Human Genetics, 88, 344–346.CrossRefGoogle ScholarPubMed
Golub, A. L., & Johnson, B. D. (1998). Alcohol is not the gateway to hard drug abuse. Journal of Drug Issues, 28, 971–985.CrossRefGoogle Scholar
Goodwin, D. W., Schulsinger, F., Hermansen, L., Guze, S. B., & Winokur, G. (1973). Alcohol problems in adoptees raised apart from alcoholic biological parents. Archives of General Psychiatry, 28, 238–243.CrossRefGoogle ScholarPubMed
Grant, B. F., & Dawson, D. A. (1997). Age at onset of alcohol use and its association with DSM-IV alcohol abuse and dependence: Results from the National Longitudinal Alcohol Epidemiologic Survey. Journal of Substance Abuse, 9, 103–110.CrossRefGoogle ScholarPubMed
Hays, R. D., & Ellickson, P. L. (1996). Associations between drug use and deviant behavior in teenagers. Addictive Behaviors, 21, 291–302.CrossRefGoogle ScholarPubMed
Heath, A. C., & Martin, N. G. (1988). Teenage alcohol use in the Australian twin register: Genetic and social determinants of starting to drink. Alcoholism: Clinical and Experimental Research, 12, 735–741.CrossRefGoogle ScholarPubMed
Hicks, B. M., Krueger, R. F., Iacono, W. G., McGue, M., & Patrick, C. J. (2004). Family transmission and heritability of externalizing disorders. Archives of General Psychiatry, 61, 922–928.CrossRefGoogle ScholarPubMed
Higuchi, S., Matsushita, S., Imazeki, H., Kinoshita, T., Takagi, S., & Kono, H. (1994). Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet, 343, 741–742.CrossRefGoogle ScholarPubMed
Higuchi, S., Matsushita, S., Masaki, T., Yokoyama, A, Kimura, M., Suzuki, G., et al. (2004). Influence of genetic variations of ethanol-metabolizing enzymes on phenotypes of alcohol-related disorders. Annals of the New York Academy of Sciences, 1025, 472–480.CrossRefGoogle ScholarPubMed
Higuchi, S., Matsushita, S., Muramatsu, T., Takagi, S., & Hayashida, M. (1995). Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism. American Journal of Psychiatry, 152, 1219–1221.Google ScholarPubMed
Hopfer, C. J., Timberlake, D., Haberstick, B., Lessem, J. M., Ehringer, M. A., Smolen, A., et al. (2005). Genetic influences on quantity of alcohol consumed by adolescents and young adults. Drug and Alcohol Dependence, 78, 187–193.CrossRefGoogle ScholarPubMed
Iacono, W. G., Carlson, S. R., Taylor, J., Elkins, I. J., & McGue, M. (1999). Behavioral disinhibition and the development of substance-use disorders: Findings from the Minnesota Twin Family Study. Development and Psychopathology, 11, 869–900.CrossRefGoogle ScholarPubMed
Iacono, W. G., Malone, S. M., & McGue, M. (2003). Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude. International Journal of Psychophysiology, 48, 147–178.CrossRefGoogle ScholarPubMed
Jessor, R. (1991). Successful adolescent development among youth in high-risk settings. American Psychologist, 48, 117–126.CrossRefGoogle Scholar
Jessor, R., & Jessor, S. L. (1977). Problem behavior and psychosocial development: A longitudinal study of youth. New York: Academic Press.Google Scholar
Kandel, D. B., Johnson, J. G., Bird, H. R., Weissman, M. M., Goodman, S. H., Lahey, B. B. et al. , (1999). Psychiatric comorbidity among adolescents with substance use disorders: Findings from the MECA study. Journal of the American Academy of Child & Adolescent Psychiatry, 38, 693–699.CrossRefGoogle ScholarPubMed
Kandel, D., & Yamaguchi, K. (1993). From beer to crack: Developmental patterns of drug involvement. American Journal of Public Health, 83, 851–855.CrossRefGoogle ScholarPubMed
Kandel, D. B., Yamaguchi, K., & Chen, K. (1992). Stages of progression in drug involvement from adolescence to adulthood: Further evidence for the gateway theory. Journal of Studies on Alcohol, 53, 447–457.CrossRefGoogle ScholarPubMed
Kandel, D. B., Yamaguchi, K., & Klein, L. C. (2006). Testing the gateway hypothesis. Addiction, 101, 470–476.CrossRefGoogle ScholarPubMed
Kendler, K. S., Davis, C. G., & Kessler, R. C. (1997). The familiar aggregation of common psychiatric and substance use disorders in the National Comorbidity Survey: A family history study. British Journal of Psychiatry, 170, 541–548.CrossRefGoogle Scholar
Krueger, R. F., Hicks, B. M., Patrick, C. J., Carlson, S. R., Iacono, W. G., & McGue, M. (2002). Etiologic connections among substance dependence, antisocial behavior, and personality: Modeling the externalizing spectrum. Journal of Abnormal Psychology, 111, 411–424.CrossRefGoogle ScholarPubMed
Krueger, R. F., Markon, K. E., Patrick, C. J., & Iacono, W. G. (2005). Externalizing psychopathology in adulthood: A dimensional conceptualization and its implications for DSM-V. Journal of Abnormal Psychology, 114, 537–550.CrossRefGoogle ScholarPubMed
Lee, H. C., Lee, H. S., Jung, H. S., Yi, S. Y., Jung, H. K., Yoon, J. H., et al. (2001). Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population. Journal of Korean Medical Science, 16, 745–750.CrossRefGoogle Scholar
Luczak, S. E., Wall, T. L., Cook, T. A. R., Shea, S. H., & Carr, L. G. (2004). ALDH2 status and conduct disorder mediate the relationship between ethnicity and alcohol dependence in Chinese, Korean, and white American college students. Journal of Abnormal Psychology, 113, 271–278.CrossRefGoogle ScholarPubMed
Luczak, S. E., Glatt, S. J., & Wall, T. L. (2006). Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians. Psychological Bulletin, 132, 607–621.CrossRefGoogle ScholarPubMed
Matsuo, K., Hamajima, N., Shinoda, M., Hatooka, S., Inoue, M., Takezaki, T., et al. (2001). Gene–environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis, 22, 913–916.CrossRefGoogle ScholarPubMed
McGue, M., & Iacono, W. G. (2005). The association of early adolescent problem behavior with adult psychopathology. American Journal of Psychiatry, 162, 1118–1124.CrossRefGoogle ScholarPubMed
McGue, M., Iacono, W. G., & Krueger, R. (2006). The association of early adolescent problem behavior and adult psychopathology: A multivariate behavioral genetic perspective. Behavior Genetics, 36, 591–602.CrossRefGoogle ScholarPubMed
McGue, M., Iacono, W. G., Legrand, L. N., & Elkins, I. (2001). The origins and consequences at age at first drink. I. Associations with substance-use disorders, disinhibitory behavior and psychopathology, and P3 amplitude. Alcoholism—Clinical and Experimental Research, 25, 1156–1165.Google ScholarPubMed
McGue, M., Keyes, M., Sharma, A., Elkins, I., Legrand, L., Johnson, W., et al. (2007). The environments of adopted and non-adopted youth: Evidence on range restriction from the Sibling Interaction and Behavior Study (SIBS). Behavior Genetics, 37, 449–462.CrossRefGoogle ScholarPubMed
McGue, M., Sharma, A., & Benson, P. (1996a). The effect of common rearing on adolescent adjustment: Evidence from a U.S. adoption cohort. Developmental Psychology, 32, 604–613.CrossRefGoogle Scholar
McGue, M., Sharma, A., & Benson, P. (1996b). Parent and sibling influences on adolescent alcohol use and misuse: Evidence from a U.S. adoption cohort. Journal of Studies on Alcohol, 57, 8–18.CrossRefGoogle Scholar
Nigg, J. T. (2000). On inhibition/disinhibition in developmental psychopathology: Views from cognitive and personality psychology and a working inhibition taxonomy. Psychological Bulletin, 126, 220–246.CrossRefGoogle Scholar
O'Malley, P. M., Johnston, L. D., & Bachman, J. G. (1998). Alcohol use among adolescents. Alcohol Health & Research World, 22, 85–93.Google ScholarPubMed
Peele, S., & Brodsky, A. (1997). Gateway to nowhere: How alcohol came to be scapegoated for drug abuse. Addiction Research, 5, 419–426.CrossRefGoogle Scholar
Robins, L. M., Baber, T., & Cottler, L. B. (1987). Composite International Diagnostic Interview: Expanded substance abuse module. St. Louis, MO: Author.Google Scholar
Rutter, M., Pickles, A., Murray, R., & Eaves, L. J. (2001). Testing hypotheses on specific causal effects on behavior. Psychological Bulletin, 127, 291–324.CrossRefGoogle ScholarPubMed
Rutter, M., & Silberg, J. (2002). Gene–environment interplay in relation to emotional and behavioral disturbance. Annual Review of Psychology, 53, 463–490.CrossRefGoogle ScholarPubMed
Shedler, J., & Block, J. (1990). Adolescent drug use and psychological health: A longitudinal inquiry. American Psychologist, 45, 612–630.CrossRefGoogle ScholarPubMed
Sher, K. J., & Trull, T. J. (1994). Personality and disinhibitory psychopathology: Alcoholism and antisocial personality disorder. Journal of Abnormal Psychology, 103, 92–102.CrossRefGoogle ScholarPubMed
Slomkowski, C., Rende, R., Conger, K. J., Simons, R. L., & Conger, R. D. (2001). Sisters, brothers, and delinquency: Evaluating social influence during early and middle adolescence. Child Development, 72, 271–283.CrossRefGoogle ScholarPubMed
Slomkowski, C., Rende, R., Novak, S., Lloyd-Richardson, E., & Niaura, R. (2005). Sibling effects on smoking in adolescence: Evidence for social influence from a genetically informative design. Addiction, 100, 430–438.CrossRefGoogle ScholarPubMed
Slutske, W. S., Heath, A. C., Madden, P. A. F., Bucholz, K. K., Statham, D. J., & Martin, N. G. (2002). Personality and the genetic risk for alcohol dependence. Journal of Abnormal Psychology, 111, 124–133.CrossRefGoogle ScholarPubMed
Stallings, M. C., Corley, R. P., Dennehy, B., Hewitt, J. K., Krauter, K. S., Lessem, J. M., et al. (2005). A genome-wide search for quantitative trait loci that influence antisocial drug dependence in adolescence. Archives of General Psychiatry, 62, 1042–1051.CrossRefGoogle ScholarPubMed
Takeshita, T., Morimoto, K., Mao, X. Q., Hashimoto, T., & Furuyama, J. I. (1994). Characterization of the three genotypes of low Km aldehyde dehydgrogenase in a Japanese population. Human Genetics, 94, 217–223.CrossRefGoogle Scholar
Thomas, D. C. (2004). Statistical methods in genetic epidemiology. New York: Oxford University Press.CrossRefGoogle Scholar
Urberg, K. A., Degirmencioglu, S. M., & Pilgrim, C. (1997). Close friend and group influence on adolescent cigarette smoking and alcohol use. Developmental Psychology, 33, 834–844.CrossRefGoogle ScholarPubMed
Wall, T. L., Shea, S. H., Chan, K. K., & Carr, L. G. (2001). A genetic association with the development of alcohol and other substance use behavior in Asian Americans. Journal of Abnormal Psychology, 110, 173–178.CrossRefGoogle ScholarPubMed
Wang, R. S., Nakajima, T., Kawamoto, T., & Honma, T. (2002). Effects of aldehyde dehydrogenase-2 genetic polymorphisms on metabolism of structurally different aldehydes in human liver. Drug Metabolism and Disposition, 30, 69–73.CrossRefGoogle ScholarPubMed
Yamaguchi, K., & Kandel, D. B. (1984). Patterns of drug use from adolescence to young adulthood—III. Predictors of progression. American Journal of Public Health, 74, 673–681.CrossRefGoogle ScholarPubMed
Young, S. E., Stallings, M. C., Corley, R. P., Krauter, K. S., & Hewitt, J. K. (2000) Genetic and environmental influences on behavioral disinhibition. American Journal of Medical Genetics, 96, 684–695.3.0.CO;2-G>CrossRefGoogle ScholarPubMed