Skip to main content Accessibility help

Associations between alcohol dehydrogenase genes and alcohol use across early and middle adolescence: Moderation × Preventive intervention

  • H. Harrington Cleveland (a1), Gabriel L. Schlomer (a1), David J. Vandenbergh (a1), Pedro S. A. Wolf (a1), Mark E. Feinberg (a1), Mark T. Greenberg (a1), Richard L. Spoth (a2) and Cleve Redmond (a2)...


Data from the in-school sample of the PROSPER preventive intervention dissemination trial were used to investigate associations between alcohol dehydrogenase genes and alcohol use across adolescence, and whether substance misuse interventions in the 6th and 7th grades (targeting parenting, family functioning, social norms, youth decision making, and peer group affiliations) modified associations between these genes and adolescent use. Primary analyses were run on a sample of 1,885 individuals and included three steps. First, we estimated unconditional growth curve models with separate slopes for alcohol use from 6th to 9th grade and from 9th to 12th grade, as well as the intercept at Grade 9. Second, we used intervention condition and three alcohol dehydrogenase genes, 1B (ADH1B), 1C (ADH1C), and 4 (ADH4) to predict variance in slopes and intercept. Third, we examined whether genetic influences on model slopes and intercepts were moderated by intervention condition. The results indicated that the increase in alcohol use was greater in early adolescence than in middle adolescence; two of the genes, ADH1B and ADH1C, significantly predicted early adolescent slope and Grade 9 intercept, and associations between ADH1C and both early adolescent slope and intercept were significantly different across control and intervention conditions.


Corresponding author

Address correspondence and reprint requests to: H. Harrington Cleveland, Department of Human Development and Family Studies, Pennsylvania State University, 315 East Human Development Building, University Park, PA 16802; E-mail:


Hide All

We thank Dr. Deborah Grove, Kerry Hair, and Ashley Price of the Penn State Genomics Core Facility for DNA purification and genotyping and Lee Carpenter and Amanda Griffin for their assistance in preparing the document. Work on this paper was supported by the National Institute on Drug Abuse (Grants DA030389 and DA013709).



Hide All
Agrawal, A., Balasubramanian, S., Smith, E., Madden, P., Bucholz, K., Heath, A., & Linskey, M. T. (2010). Peer substance involvement modifies genetic influences on regular substance involvement in young women. Addiction, 105, 18441853.
Albert, D., Belsky, D., Crowley, D. M., Latendresse, S. J., Aliev, F., Riley, B., … Dodge, K. (2015). Can genetics predict response to complex behavioral interventions? Evidence from a genetic analysis of the Fast Track randomized control trial. Journal of Policy Analysis and Management, 34, 497518.
Ali, M. A., Way, M. J., Marks, M., Guerrini, I., Thomson, A. D., Strang, J., … Morgan, M. Y. (2015). Phenotypic heterogeneity in study populations may significantly confound the results of genetic association studies on alcohol dependence. Psychiatric Genetics, 25, 234240.
Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2015). The hidden efficacy of interventions: Gene × Environment experiments from a differential susceptibility perspective. Annual Review of Psychology, 66, 381409.
Bakermans-Kranenberg, M. J., van IJzendoorn, M. H., Pijlman, F. T. A., Mesman, J., & Juffer, F. (2008). Experimental evidence for differential susceptibility: Dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers’ externalizing behavior in a randomized controlled trial. Developmental Psychology, 44, 293300.
Belsky, D. W., Moffitt, T. E., Baker, T., Biddle, A. H., Evans, J. P., Harintno, H., … Caspi, A. (2013). Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: Evidence from a 4-decade longitudinal study. JAMA Psychiatry, 70, 534542.
Belsky, J., & Pluess, M. (2009). Beyond diathesis stress: Differential susceptibility to environmental influences. Psychological Bulletin, 135, 885.
Belsky, J., & Pluess, M. (2013). Beyond risk, resilience and dysregulation: Phenotypic plasticity and human development. Development and Psychopathology, 25, 12431261.
Belsky, J., & van IJzendoorn, M. H. (2015). What works for whom? Genetic moderation of intervention efficacy. Development and Psychopathology, 27, 16. doi:10.1017/S0954579414001254.
Berrettini, W. H., & Doyle, G. A. (2012). The CHRNA5-A3-B4 gene cluster in nicotine addiction. Molecular Psychiatry, 17, 856866.
Biernacka, J. M., Geske, J. R., Schneekloth, T. D., Frye, M. A., Cunningham, J. M., Choi, D. S., … Karpyak, V. M. (2013). Replication of genome wide association studies of alcohol dependence: Support for association with variation in ADH1C. PLOS ONE, 8, e58798. doi:10.1371/journal.pone.0058798
Birley, A. J., Whitfield, J. B., Neale, M. C., Duffy, D. L., Heath, A. C., Boomsma, D. I., & Martin, N. G. (2005). Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci. Behavioral Genetics, 35, 509524.
Botvin, G. J. (2000). Preventing adolescent drug abuse through life skills training: Theory, methods, and effectiveness. In Hansen, W. B., Giles, S. M., & Fearnow-Kenney, M. D. (Eds.), Improving prevention effectiveness (pp. 225257). Greensboro, NC: Tanglewood Research.
Brody, G. H., Beach, S. R. H., Philibert, R. A., Chen, Y., & Murry, V. M. (2009). Prevention effects moderate the association of 5-HTTLPR and youth risk behavior initiation: Gene × Environment hypotheses tested via a randomized prevention design. Child Development, 80, 645661.
Centers for Disease Control and Prevention. (1991). Alcohol-related traffic fatalities among youth and young adults: United States, 1982–1989. Morbidity and Mortality Weekly Report, 40, 178–179, 185187.
Chang, C. C., Chow, C. C., Tellier, L. C. A. M., Vattikuit, S., Purcell, S. M., & Lee, J. J. (2015). Second generation PLINK: Rising to the challenge of larger and richer datasets. GigaScience, 4, 116. doi:10.1186/s13742-015-0047-8
Clark, D. B., Parker, A. M., & Lynch, K. G. (1999). Psychopathogy and substance-related problems during early adolescence: A survival analysis. Journal of Clinical Child Psychology, 28, 333341.
Cleveland, H. H., Griffin, A., Wolf, P. A., Wiebe, R. P., Schlomer, G. L., Feinberg, M., … Vandenbergh, D. J. (in press). Transactions between substance use intervention, the oxytocin receptor (OXTR) gene, and peer substance use predicting youth alcohol use. Prevention Science. doi:10.1007/s11121-017-0749-5
Cleveland, H. H., Schlomer, G. L., Vandenbergh, D. J., Feinberg, M., Greenberg, M., Spoth, R.Hair, K. L. (2015). The conditioning of intervention effects on early adolescent alcohol use by maternal involvement and dopamine receptor D4 (DRD4) and serotonin transporter linked polymorphic region (5-HTTLPR) genetic variants. Development and Psychopathology, 27, 5167. doi:10.1017/s0954579414001291
Cleveland, H. H., & Wiebe, R. (2008). Understanding the progression from adolescent marijuana use to young adult serious drug use: Gateway effect or developmental trajectory? Development and Psychopathology, 20, 615632.
Cleveland, H. H., Schlomer, G. L., Vandenbergh, D. J., Feinberg, M., Greenberg, M., Spoth, R., … Hair, K. L. (2015). The conditioning of intervention effects on early adolescent alcohol use by maternal involvement and dopamine receptor D4 (DRD4) and serotonin transporter linked polymorphic region (5-HTTLPR) genetic variants. Development and Psychopathology, 27, 5167. doi:10.1017/s0954579414001291
Cleveland, H. H., Zheng, Y., Wiebe, R., & McGuire, J. (2015). Predicting the drinking of minority adolescents from their exposure to White schoolmates: Differences and similarities between Hispanic, Black, and Asian adolescents. Journal of Ethnicity in Substance Use, 14, 166186. doi:10.1080/15332640.2014.973626
Dobkin, P. I., Tremblay, R. A., & Masse, L. C. (1995). Individual and peer characteristics in predicting boys’ early onset of substance abuse: A seven-year longitudinal study. Child Development, 28, 11981214
Edenberg, H. J., & Foroud, T. (2014). Genetics of alcoholism in alcohol and the nervous system. In Sullivan, E. V. & Pfefferbaum, A. (Eds.), Handbook of clinical neurology (Vol. 125, 3rd series, pp. 561571). New York: Elsevier.
Edenberg, H. J., Jerome, R. E., & Li, M. (1999). Polymorphism of the human alcohol dehydrogenase 4 (ADH4) promoter affects gene expression. Pharmacogenetics, 9, 2530.
Ellickson, P. L., McCaffrey, D. F., Ghosh-Dastidar, B., & Longshore, D. L. (2003). New inroads in preventing adolescent drug use: Results from a large-scale trial of Project ALERT in middle schools. American Journal of Public Health, 93, 18301836.
Ellis, B. J., Boyce, W. T., Belsky, J., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2011). Differential susceptibility to the environment: An evolutionary–neurodevelopmental theory. Development and Psychopathology, 23, 728.
Gottesman, I. I., & Gould, T. D. (2003). The endophenotype concept in psychiatry: Etymology and strategic intentions. American Journal of Psychiatry, 160, 636645.
Grochans, E., Grzywacz, A., Małecka, I., Samochowiec, A., Karakiewicz, B., & Samochowiec, J. (2011). Research on associations between selected polymorphisms of genes DRD2, 5HTT, GRIK3, ADH4 and alcohol dependence syndrome. Psychiatria Polska (Warszawa) , 45, 325335.
Guindalini, C., Scivoletto, S., Ferreira, R. G., Breen, G., Zilberman, M., Peluso, M. A., & Zatz, M. (2005). Association of genetic variants in alcohol dehydrogenase 4 with alcohol dependence in Brazilian patients. American Journal of Psychiatry, 162, 10051007.
Halder, I., Shriver, M., Thomas, M., Fernandez, J. R., & Frudakis, T. (2008). A panel of ancestry informative markers for estimating individual biogeographical ancestry and admixture from four continents: Utility and applications. Human Mutation, 29, 648658.
Hawkins, J. D., Graham, J. W., Maguin, E., Abbott, R., Hill, K. G., & Catalano, R. F. (1997). Exploring the effects of age of alcohol use initiation and psychosocial risk factors on subsequent misuse. Journal of Studies on Alcohol, 58, 280290.
Hingson, R. W., & Zha, W. (2009). Age of drinking onset, alcohol use disorders, frequent heavy drinking, and unintentionally injuring oneself and others after drinking. Pediatrics, 123, 14771484. doi:10.1542/peds.2008-2176
Hurley, T. D., Edenberg, H., & Li, T.-K. (2002). The pharmacogenomics of alcoholism. In Licinio, J. & Wong, M.-L. (Eds.), Pharmacogenomics: The search for individualized therapies. Weinheim, Germany: Wiley-VCH.
Jessor, R., & Jessor, S. L. (1977). Problem behavior and psychosocial development: A longitudinal study of youth. New York: Academic Press.
Johnston, L. D., O'Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (2006). Monitoring the future: National survey results on drug use, 1975–2005: Vol. 1. Secondary school students. Bethesda, MD: National Institute on Drug Abuse.
Keyes, M. A., Iacono, W. G., & McGue, M. (2007). Early onset problem behavior, young adult psychopathology, and contextual risk. Twin Research and Human Genetics, 10, 4553.
Kuo, P. H., Kalsi, G., Prescott, C. A., Hodgkinson, C. A., Goldman, D., van den Oord, E. J., … Riley, B. P. (2008). Association of ADH and ALDH genes with alcohol dependence in the Irish Affected Sib Pair Study of alcohol dependence (IASPSAD) sample. Alcohol Clinical & Experimental Research, 32, 785795.
Kuryatov, A., Berrettini, W., & Lindstrom, J. (2001). Acetylcholine receptor (AChR) α5 subunit variant associated with risk for nicotine dependence and lung cancer reduces (α4β2)2α5 AChR function. Molecular Pharmacology, 79, 119125.
Li, M., & Edenberg, H. J. (2009). Function of cis-acting elements in human alcohol dehydrogenase 4 (ADH4) promoter and role of C/EBP proteins in gene expression. DNA and Cell Biology, 17, 387397.
Lo, C. C. (2000). Timing of drinking initiation: A trend study predicting drug use among high school. Journal of Drug Issues, 30, 525554.
Luo, X., Kranzler, H. R., Zuo, L., Lappalainen, J., Yang, B. Z., & Gelernter, J. (2006). ADH4 gene variation is associated with alcohol dependence and drug dependence in European Americans: Results from HWD tests and case-control association studies. Neuropsychopharmacology, 31, 10851095.
Luo, X., Kranzler, H. R., Zuo, L., Wang, S., Schork, N. J., & Gelernter, J. (2007). Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans. Human Molecular Genetics, 16, 380390.
Luo, X., Kranzler, H. R., Zuo, L., Yang, B. Z., Lappalainen, J., & Gelernter, J. (2005). ADH4 gene variation is associated with alcohol and drug dependence: Results from family controlled and population-structured association studies. Pharmacogenetics and Genomics, 15, 755768.
Macgregor, S., Lind, P. A., Bucholz, K. K., Hansell, N. K., Madden, P. A., Richter, M. M., … Whitfield, J. B. (2009). Associations of ADH and ALDH2 gene variation with self-report alcohol reactions, consumption and dependence: An integrated analysis. Human Molecular Genetics, 18, 580593. doi:10.1093/hmg/ddn372
McClelland, G. H., & Judd, C. M. (1993). Statistical difficulties of detecting interactions and moderator effects. Psychological Bulletin, 114, 376390.
McGue, M., Iacono, W. G., Legrand, L. N., & Elkins, I. (2001). Origins and consequences of age at first drink: II. Familial risk and heritability. Alcohol Clinical and Experimental Research, 25, 11661173.
McNeal, R. B. Jr., Hansen, W. B., Harrington, N. G., & Giles, S. M. (2004). How All Stars works: An examination of program effects on mediating variables. Health Education & Behavior, 31, 165178.
Meyers, J. L., & Dick, D. M. (2010). Genetic and environmental risk factors for adolescent-onset substance use disorders. Child Adolescent Psychiatric Clinics North America, 19, 465477.
Muthén, L. K., & Muthén, B. O. (1998–2015). Mplus user's guide (7th ed.). Los Angeles: Author.
Nikolova, Y. S., Ferrell, R. E., Manuck, S. B., & Hariri, A. R. (2011). Multilocus genetic profile for dopamine signaling predicts ventral striatum reactivity. Neuropsychopharmacology, 36, 19401947.
Olfson, E., Edenberg, H. J., Nurnberger, J. Jr., Agrawal, A., Bucholz, K. K., Almasy, L. A., … Bierut, L. J. (2014). An ADH1B variant and peer drinking in progression to adolescent drinking milestones: Evidence of a gene-by-environment interaction. Alcohol Clinical and Experimental Research, 38, 25412549. doi:10.1111/acer.12524
Osier, M. V., Pakstis, A. J., Soodyall, H., Comas, D., Goldman, D., Odunsi, A., … Kidd, K. K. (2002). A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity. American Journal of Human Genetics, 71, 8499.
Parker, D. A., Levin, B. M., & Harford, T. C. (1996). Effects of early drinking and an antisocial orientation on the alcohol use of young Russians. Alcohol Clinical and Experimental Research, 20, 11791183.
Pikanen, T., Lyyra, A. L., & Pulkkinen, L (2005). Age of onset of drinking and the use of alcohol in adulthood: A follow-up study from age 8–42 for females and males. Addiction, 100, 652661.
Preuss, U. W., Ridinger, M., Rujescu, D., Samochowiec, J., Fehr, C., Wurst, F. M., … Zill, P. (2011). Association of ADH4 genetic variants with alcohol dependence risk and related phenotypes: Results from a larger multicenter association study. Addiction Biology, 16, 323333.
Purcell, S. M., & Chang, C. C. (2015). PLINK 1.9. Retrieved from
Rose, R. J., Dick, D. M., Viken, R. J., Pulkkinen, L., & Kapio, J (2001) Drinking or abstaining at age 14: A genetic epidemiological study. Alcohol: Clinical and Experimental Research, 25, 15941604.
Saccone, S. F., Hinrichs, A. L., Saccone, N. L., Chase, G. A., Konvicka, K., Madden, P. A., … Bierut, L. J. (2007). Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics, 16, 3649.
Salvatore, J. E., & Dick, D. M. (2015). Gene-environment interplay: Where we are, where we are going. Journal of Marriage and Family, 77, 344350. doi:10.1111/jomf.12164
Sampson, H. H., Maxell, C. O., & Doyle, T. F. (1989). The relation of initial alcohol experiences to current alcohol consumption. Journal of Studies on Alcohol, 50, 254260.
Sartor, C. E., Lynskey, M. T., Bucholz, K. K., Madden, P. A. F., Martin, N. G., & Heath, A. C. (2009). Timing of first alcohol use and alcohol dependence: Evidence of common genetic influences. Addiction, 104, 15121518.
SAS Institute. (2012). SAS/STAT 9.4 users guide: Survey data analysis. Cary, NC: Author.
Schlomer, G. L., Bauman, S., & Card, N. A. (2010). Best practices for missing data management in counseling psychology. Journal of Counseling Psychology, 57, 110. doi:10.1037/a0018082
Schlomer, G. L., Cleveland, H. H., Vandenbergh, D. J., Fosco, G. M., & Feinberg, M. E. (2015). Looking forward in candidate gene research: Concerns and suggestions. Journal of Marriage and Family, 77, 351354. doi:10.1111/jomf.12165
Schlomer, G. L., Fosco, G. M., Cleveland, H. H., Vandenbergh, D. J., & Feinberg, M. E. (2015). Interparental relationship sensitivity leads to adolescent internalizing problems: Different genotypes, different pathways. Journal of Marriage and Family, 77, 329343. doi:10.1111/jomf.12168
Schulenberg, L. E., & Maggs, J. L. (2002). A developmental perspective on alcohol use and heaving drinking during adolescence and the transition to young adulthood. Journal of Studies on Alcohol, 14, 5470.
Spear, L. P. (2015). Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence? Physiology & Behavior, 148, 122130. doi:10.1016/j.physbeh.2015.01.027
Spoth, R., Greenberg, M., Bierman, K., & Redmond, C. (2004). PROSPER community-university partnership model for public education systems: Capacity-building for evidence-based, competence-building prevention. Prevention Science, 5, 3139.
Spoth, R., Guyll, M., Lillehoj, C. J., Redmond, C., & Greenberg, M. (2007). PROSPER study of evidence-based intervention implementation quality by community-university partnerships. Journal of Community Psychology, 35, 981999. doi:10.1002/jcop.20207
Spoth, R., Redmond, C., Clair, S., Shin, C., Greenberg, M., & Feinberg, M. (2011). Preventing substance misuse through community-university partnerships: Randomized controlled trial outcomes 4½ years past baseline. American Journal of Preventive Medicine, 40, 440447.
Stueve, A., & O'Donnell, L. N. (2005). Early alcohol initiation and subsequent sexual and alcohol risk behaviors among urban youths. American Journal of Public Health, 95, 887893.
Substance Abuse and Mental Health Services Administration. (2006). Results from the 2005 National Survey on Drug Use and Health: National findings (Office of Applied Studies, NSDUH Series H-30, DHHS Publication No. SMA 06-4194). Rockville, MD: Author.
Tolstrup, J. S., Nordestgaard, B. G., Rasmussen, S., Tybjaerg-Hansen, A., & Grønbaek, M. (2008). Alcoholism and alcohol drinking habits predicted from alcohol dehydrogenase genes. Pharmacogenomics Journal, 8, 220–207.
Treutlein, J., Cichon, S., Ridinger, M., Wodarz, N., Soyka, M., Zill, P., … Rietschel, M. (2009). Genome-wide association study of alcohol dependence. Archives of General Psychiatry, 66, 773784. doi:10.1001/archgenpsychiatry.2009.83
Tsukahara, M., & Yoshida, A. (1989). Chromosomal assignment of the alcohol dehydrogenase cluster locus to human chromosome 4q21-23 by in situ hybridization. Genomics, 4, 218220.
Vandenbergh, D. J., Schlomer, G. L., Cleveland, H. H., Schink, A. E., Feinberg, M. E., Neiderhiser, J. M., … Redmond, C. (2016). An adolescent drug use intervention blocks the effect of CHRNA5 genotype on smoking in high school. Nicotine & Tobacco Research, 18, 212220. doi:10.1093/ntr/ntv095
Wall, T. L., Luczak, S. E., Orlowska, D., & Pandika, D. (2013). Differential metabolism of alcohol as an intermediate phenotype of risk for alcohol use disorders: Alcohol and aldehyde dehydrogenase variants. In MacKillop, J. & Munafò, M. R. (Eds.), Genetic influences on addiction: An intermediate phenotype approach (pp. 4163). Cambridge, MA: MIT Press.
Wang, J. C., Kapoor, M., & Goate, A. M. (2012). The genetics of substance dependence. Annual Review of Genomics and Human Genetics, 13, 241261. doi:10.1146/annurev-genom-090711-163844
Way, M., McQuillin, A., Saini, J., Ruparelia, K., Lydall, G. J., Guerrini, I., … Gurling, H. M. (2015). Genetic variants in or near ADH1B and ADH1C affect susceptibility to alcohol dependence in a British and Irish population. Addiction Biology, 20, 594604.
Werner, M. J., Walker, L. S., & Greee, J. W. (1994). Longitudinal evaluation of a screening measure for problem drinking among female college freshman. Archives of Pediatrics and Adolescent Medicine, 148, 13311337.
Widaman, K. F., Helm, J. L., Castro-Schilo, L., Pluess, M., Stallings, M. C., & Belsky, J. (2012). Distinguishing ordinal and disordinal interactions. Psychological Methods, 17, 615622.
Windle, M. (2004). Suicidal behaviors and alcohol use among adolescents: A developmental psychopathology perspective. Alcohol Clinical and Experimental Research, 28(Suppl.), 29S37S.
Yang, J., Lee, S. H., Goddard, M. E., & Visscher, P. M. (2011). GCTA: A tool for genome-wide complex trait analysis. American Journal of Human Genetics, 88, 7682.
Ystrom, E., Kenneth, S., Kendler, K. S., & Reichborn-Kjennerud, T. (2014). Early age of alcohol initiation is not the cause of alcohol use disorders in adulthood, but is a major indicator of genetic risk: A population-based twin study. Addiction, 109, 18241832.
Zucker, R. A. (2006). Alcohol use and the alcohol use disorders: A developmental-biopsychological systems formulation covering the life course. In Cicchetti, D. & Cohen, D. J. (Eds.), Developmental psychopathology: Vol. 3. Risk, disorder and adaptation (2nd ed., pp. 620656). Hoboken, NJ: Wiley.
Zucker, R. A., Donovan, J. E., Masten, A. S., Mattson, M. E., & Moss, H. (2008). Early developmental processes and the continuity of risk for underage drinking and problem drinking. Pediatrics, 121(Suppl. 4), S252S272.


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed