Development and Psychopathology

Research Article

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

Daniel E. Ironsa1 c1, Matt McGuea1, William G. Iaconoa1 and William S. Oettinga1

a1 University of Minnesota


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.


c1 Address correspondence and reprint requests to: Daniel Irons, Department of Psychology, University of Minnesota, 75 East River Road, Minneapolis, MN 55455; E-mail:


This work was supported in part by USPHS Grants AA11886 and MH066140, and NCRR/NIH Grant M01-RR00400.