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

  • Daniel E. Irons (a1), Matt McGue (a1), William G. Iacono (a1) and William S. Oetting (a1)
  • DOI:
  • Published online: 11 October 2007

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.

Corresponding author
Address correspondence and reprint requests to: Daniel Irons, Department of Psychology, University of Minnesota, 75 East River Road, Minneapolis, MN 55455; E-mail:
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

N. D. Brener , & J. L. Collins (1998). Co-occurrence of health-risk behaviors among adolescents in the United States. Journal of Adolescent Health, 22, 209213.

P. Brennan (2004). Commentary: Mendelian randomization and gene–environment interaction. International Journal of Epidemiology, 33, 1721.

J. F. Brien , & C. W. Loomis (1983). Pharmacology of acetaldehyde. Canadian Journal of Physiology and Pharmacology, 61, 122.

C. R. Cloninger , M. Bohman , & S. Sigvardsson (1981). Inheritance of alcohol abuse. Cross-fostering analysis of adopted men. Archives of General Psychiatry, 38, 861868.

G. Davey Smith , & S. Ebrahim (2005). What can Mendelian randomisation tell us about modifiable behavioural and environmental exposures? British Medical Journal, 330, 10761079.

V. B. Faden (2006). Trends in initiation of alcohol use in the united states 1975 to 2003. Alcoholism-Clinical and Experimental Research, 30, 10111022.

H. B. Gibson (1967). Self-reported delinquency among schoolboys, and their attitudes to the police. British Journal of Social and Clinical Psychology, 6, 168173.

H. W. Goedde , D. P. Agarwal , G. Fritze , D. Meier-Tackmann , S. Singh , G. Beckmann , (1992). Distribution of ADH2 and ALDH2 genotypes in different populations. Human Genetics, 88, 344346.

A. L. Golub , & B. D. Johnson (1998). Alcohol is not the gateway to hard drug abuse. Journal of Drug Issues, 28, 971985.

D. W. Goodwin , F. Schulsinger , L. Hermansen , S. B. Guze , & G. Winokur (1973). Alcohol problems in adoptees raised apart from alcoholic biological parents. Archives of General Psychiatry, 28, 238243.

B. F. Grant , & D. A. Dawson (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, 103110.

R. D. Hays , & P. L. Ellickson (1996). Associations between drug use and deviant behavior in teenagers. Addictive Behaviors, 21, 291302.

A. C. Heath , & N. G. Martin (1988). Teenage alcohol use in the Australian twin register: Genetic and social determinants of starting to drink. Alcoholism: Clinical and Experimental Research, 12, 735741.

B. M. Hicks , R. F. Krueger , W. G. Iacono , M. McGue , & C. J. Patrick (2004). Family transmission and heritability of externalizing disorders. Archives of General Psychiatry, 61, 922928.

S. Higuchi , S. Matsushita , H. Imazeki , T. Kinoshita , S. Takagi , & H. Kono (1994). Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet, 343, 741742.

S. Higuchi , S. Matsushita , T. Masaki , A Yokoyama , M. Kimura , G. Suzuki , (2004). Influence of genetic variations of ethanol-metabolizing enzymes on phenotypes of alcohol-related disorders. Annals of the New York Academy of Sciences, 1025, 472480.

C. J. Hopfer , D. Timberlake , B. Haberstick , J. M. Lessem , M. A. Ehringer , A. Smolen , (2005). Genetic influences on quantity of alcohol consumed by adolescents and young adults. Drug and Alcohol Dependence, 78, 187193.

W. G. Iacono , S. R. Carlson , J. Taylor , I. J. Elkins , & M. McGue (1999). Behavioral disinhibition and the development of substance-use disorders: Findings from the Minnesota Twin Family Study. Development and Psychopathology, 11, 869900.

W. G. Iacono , S. M. Malone , & M. McGue (2003). Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude. International Journal of Psychophysiology, 48, 147178.

R. Jessor (1991). Successful adolescent development among youth in high-risk settings. American Psychologist, 48, 117126.

D. B. Kandel , J. G. Johnson , H. R. Bird , M. M. Weissman , S. H. Goodman , B. B. Lahey , (1999). Psychiatric comorbidity among adolescents with substance use disorders: Findings from the MECA study. Journal of the American Academy of Child & Adolescent Psychiatry, 38, 693699.

D. B. Kandel , K. Yamaguchi , & K. Chen (1992). Stages of progression in drug involvement from adolescence to adulthood: Further evidence for the gateway theory. Journal of Studies on Alcohol, 53, 447457.

K. S. Kendler , C. G. Davis , & R. C. Kessler (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, 541548.

R. F. Krueger , B. M. Hicks , C. J. Patrick , S. R. Carlson , W. G. Iacono , & M. McGue (2002). Etiologic connections among substance dependence, antisocial behavior, and personality: Modeling the externalizing spectrum. Journal of Abnormal Psychology, 111, 411424.

R. F. Krueger , K. E. Markon , C. J. Patrick , & W. G. Iacono (2005). Externalizing psychopathology in adulthood: A dimensional conceptualization and its implications for DSM-V. Journal of Abnormal Psychology, 114, 537550.

H. C. Lee , H. S. Lee , H. S. Jung , S. Y. Yi , H. K. Jung , J. H. Yoon , (2001). Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population. Journal of Korean Medical Science, 16, 745750.

S. E. Luczak , T. L. Wall , T. A. R. Cook , S. H. Shea , & L. G. Carr (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, 271278.

S. E. Luczak , S. J. Glatt , & T. L. Wall (2006). Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians. Psychological Bulletin, 132, 607621.

M. McGue , & W. G. Iacono (2005). The association of early adolescent problem behavior with adult psychopathology. American Journal of Psychiatry, 162, 11181124.

M. McGue , W. G. Iacono , & R. Krueger (2006). The association of early adolescent problem behavior and adult psychopathology: A multivariate behavioral genetic perspective. Behavior Genetics, 36, 591602.

M. McGue , W. G. Iacono , L. N. Legrand , & I. Elkins (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, 11561165.

M. McGue , M. Keyes , A. Sharma , I. Elkins , L. Legrand , W. Johnson , (2007). The environments of adopted and non-adopted youth: Evidence on range restriction from the Sibling Interaction and Behavior Study (SIBS). Behavior Genetics, 37, 449462.

M. McGue , A. Sharma , & P. Benson (1996b). Parent and sibling influences on adolescent alcohol use and misuse: Evidence from a U.S. adoption cohort. Journal of Studies on Alcohol, 57, 818.

J. T. Nigg (2000). On inhibition/disinhibition in developmental psychopathology: Views from cognitive and personality psychology and a working inhibition taxonomy. Psychological Bulletin, 126, 220246.

S. Peele , & A. Brodsky (1997). Gateway to nowhere: How alcohol came to be scapegoated for drug abuse. Addiction Research, 5, 419426.

M. Rutter , A. Pickles , R. Murray , & L. J. Eaves (2001). Testing hypotheses on specific causal effects on behavior. Psychological Bulletin, 127, 291324.

M. Rutter , & J. Silberg (2002). Gene–environment interplay in relation to emotional and behavioral disturbance. Annual Review of Psychology, 53, 463490.

J. Shedler , & J. Block (1990). Adolescent drug use and psychological health: A longitudinal inquiry. American Psychologist, 45, 612630.

K. J. Sher , & T. J. Trull (1994). Personality and disinhibitory psychopathology: Alcoholism and antisocial personality disorder. Journal of Abnormal Psychology, 103, 92102.

C. Slomkowski , R. Rende , K. J. Conger , R. L. Simons , & R. D. Conger (2001). Sisters, brothers, and delinquency: Evaluating social influence during early and middle adolescence. Child Development, 72, 271283.

C. Slomkowski , R. Rende , S. Novak , E. Lloyd-Richardson , & R. Niaura (2005). Sibling effects on smoking in adolescence: Evidence for social influence from a genetically informative design. Addiction, 100, 430438.

W. S. Slutske , A. C. Heath , P. A. F. Madden , K. K. Bucholz , D. J. Statham , & N. G. Martin (2002). Personality and the genetic risk for alcohol dependence. Journal of Abnormal Psychology, 111, 124133.

M. C. Stallings , R. P. Corley , B. Dennehy , J. K. Hewitt , K. S. Krauter , J. M. Lessem , (2005). A genome-wide search for quantitative trait loci that influence antisocial drug dependence in adolescence. Archives of General Psychiatry, 62, 10421051.

T. Takeshita , K. Morimoto , X. Q. Mao , T. Hashimoto , & J. I. Furuyama (1994). Characterization of the three genotypes of low Km aldehyde dehydgrogenase in a Japanese population. Human Genetics, 94, 217223.

D. C. Thomas (2004). Statistical methods in genetic epidemiology. New York: Oxford University Press.

K. A. Urberg , S. M. Degirmencioglu , & C. Pilgrim (1997). Close friend and group influence on adolescent cigarette smoking and alcohol use. Developmental Psychology, 33, 834844.

T. L. Wall , S. H. Shea , K. K. Chan , & L. G. Carr (2001). A genetic association with the development of alcohol and other substance use behavior in Asian Americans. Journal of Abnormal Psychology, 110, 173178.

R. S. Wang , T. Nakajima , T. Kawamoto , & T. Honma (2002). Effects of aldehyde dehydrogenase-2 genetic polymorphisms on metabolism of structurally different aldehydes in human liver. Drug Metabolism and Disposition, 30, 6973.

K. Yamaguchi , & D. B. Kandel (1984). Patterns of drug use from adolescence to young adulthood—III. Predictors of progression. American Journal of Public Health, 74, 673681.

S. E. Young , M. C. Stallings , R. P. Corley , K. S. Krauter , & J. K. Hewitt (2000) Genetic and environmental influences on behavioral disinhibition. American Journal of Medical Genetics, 96, 684695.

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Development and Psychopathology
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