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Co-development of early adolescent alcohol use and depressive feelings: The role of the mu-opioid receptor A118G polymorphism

  • Marloes Kleinjan (a1) (a2), Mayke Rozing (a1), Rutger C. M. E. Engels (a1) (a2) and Maaike Verhagen (a1)

Alcohol use and depressive feelings are often related among early adolescents. However, the nature and underlying mechanisms of this association are not yet clear. The aim of this study was to investigate the co-development of alcohol use and depressive feelings over time and to examine the effects of the mu-opioid receptor (OPRM1) A118G genotype on such co-development. Data from a five-wave longitudinal, genetically informed survey study, with intervals of 4 months among a group of 739 normative early adolescents (12–13 years of age at baseline), were analyzed using a dual latent growth curve approach. OPRM1 status was evaluated from saliva-derived DNA samples. The results indicated a positive association between alcohol use and depressive feelings both at the initial levels and over time, indicating co-development in early adolescence. Compared to OPRM1 118G carriers, homozygous 118A carriers showed a greater increase in frequency of alcohol use and higher levels of depressive feelings over time. Evidence for co-development was only found within the group of homozygous 118A carriers, whereas in OPRM1 118G carriers the development of alcohol use and depressive feelings over time were not significantly associated. These results highlight the potential of OPRM1 as a common etiological factor for the development of alcohol use and depressive feelings in early adolescence.

Corresponding author
Address correspondence and reprint requests to: Marloes Kleinjan, Behavioural Science Institute, Radboud University Nijmegen, P.O. Box 9104 6500 HE, Nijmegen, The Netherlands; E-mail:
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Belendiuk, K. A., Molina, B. S., & Donovan, J. E. (2010). Concordance of adolescent reports of friend alcohol use, smoking, and deviant behavior as predicted by quality of relationship and demographic variables. Journal of Studies on Alcohol and Drugs, 711, 253257.
Berridge, K. C. (2003). Pleasures of the brain. Brain and Cognition, 52, 106128.
Bond, C., LaForge, K. S., Tian, M., Melia, D., Zhang, S., Borg, L., et al. (1998). Single-nucleotide polymorphism in the human mu-opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction. Proceedings of the National Academy of Sciences, 951, 96089613.
Brady, K. T., & Sinha, R. (2005). Co-occuring mental and substance use disorders: The neurobiological effects of chronic stress. American Journal of Psychiatry, 1621, 14831493.
Brener, N. D., Billy, J. O., & Grady, W. R. (2003). Assessment of factors affecting the validity of self-reported health-risk behavior among adolescents: Evidence from the scientific literature. Journal of Adolescent Health, 331, 436457.
Chong, R. Y., Oswald, L., Yang, X., Uhart, M., Lin, P. I., & Wand, G. S. (2006). The mu-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stress. Neuropsychopharmacology, 311, 204211.
Clark, D. B., & Bukstein, O. G. (1998). Psychopathology in adolescent alcohol abuse and dependence. Alcohol Health and Research World, 221, 117121.
Conrod, P. J., Castellanos, N., & Mackie, C. (2008). Personality-targeted interventions delay the growth of adolescent drinking and binge drinking. Journal of Child Psychiatry, 491, 181190.
Conrod, P. J., Castellanos-Ryan, N., & Strang, J. (2010). Brief, personality-targeted coping skills interventions and survival as a non-drug user over a two-year period during adolescence. Archives of General Psychiatry, 671, 8593.
Conrod, P. J., Stewart, S. H., Comeau, N., & Maclean, A. M. (2006). Efficacy of cognitive-behavioral interventions targeting personality risk factors for youth alcohol misuse. Journal of Clinical Child and Adolescents Psychology, 351, 550563.
Costello, J., Mustillo, S., Erkanli, A., Keeler, G., & Angold, A. (2003). Prevalence and development of psychiatric disorders in childhood and adolescence. Archives of General Psychiatry, 601, 837844.
Crum, R. M., Storr, C. L., Ialongo, N., & Anthony, J. C. (2008). Is depressed mood in childhood associated with an increased risk for initiation of alcohol use during early adolescence? Addictive Behaviors, 331, 2440.
Diaz, A., Simantov, E., & Rickert, V. I. (2002). Effect of abuse on health: Results of a national survey. Archives of Pediatrics and Adolescent Medicine, 1561, 811817.
Edwards, A. C., Sihvola, E., Korhonen, T., Pukkinen, L., Moilanen, I., Kaprio, J., et al. (2011). Depressive symptoms and alcohol use are genetically and environmentally correlated across adolescence. Behaviors Genetics, 411, 476488.
Engels, R. C. M. E., & Knibbe, R. A. (2000). Alcohol use and intimate relationships in adolescence: When love comes to town. Addictive Behaviors, 251, 435439.
Engels, R. C. M. E., Van der Vorst, H., Deković, M., & Meeus, W. (2007). Correspondence in collateral and self-reports on alcohol consumption: A within family analysis. Addictive Behaviors, 321, 10161030.
Fleming, C. B., Mason, W. A., Mazza, J. J., Abbott, R. D., & Catalano, R. F. (2008). Latent growth modeling of the relationship between depressive symptoms and substance use during adolescence. Psychology of Addictive Behaviors, 221, 186197.
Garriock, H. A., Tanowitz, M., Kraft, J. B., Dang, V. C., Peters, E. J., Jenkins, G. D., et al. (2010). Association of mu-opioid receptor variants and response to citalopram treatment in major depressive disorder. American Journal of Psychiatry, 1671, 565573.
Gau, S. S.Chong, M. Y., Yang, P., Yen, C. F., Liang, K. Y., & Cheng, A. T. (2007). Psychiatric and psychosocial predictors of substance use disorders among adolescents: Longitudinal study. British Journal of Psychiatry, 1901, 4248.
Gauderman, W. J., & Morrison, J. M. (2006). QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies. Retrieved from
Gelernter, J., Kranzler, H., & Cubells, J. (1999). Genetics of two mu-opioid receptor gene (OPRM1) exon I polymorphisms: Population studies, and allele frequencies in alcohol- and drug-dependent subjects. Molecular Psychiatry, 41, 476483.
Guerry, J. D., & Hastings, P. D. (2011). In search of HPA axis dysregulation in child and adolescent depression. Clinical Child and Family Psychology Review, 141, 135160.
Hankin, B. L., Abramson, L. Y., Moffit, T. E., Silva, P. A., McGee, R., & Angell, K. E. (1998). Development of depression from preadolescence to young adulthood: Emerging gender differences in a 10-year longitudinal study. Journal of Abnormal Psychology, 1071, 128140.
Hankin, B. L., Badanes, L. S., Abela, J. R., & Watamura, S. E. (2010). Hypothalamic–pituitary–adrenal axis dysregulation in dysphoric children and adolescents: Cortisol reactivity to psychosocial stress from preschool through middle adolescence. Biological Psychiatry, 681, 484490.
Hu, L., & Bentler, P. M. (1999). Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives. Structural Equation Modeling, 61, 155.
Johnston, L. D., O'Malley, P. M., & Bachman, J. G. (2001). Monitoring the Future national results on adolescent drug use: Overview of key findings, 20001 (NIH Publication No. 01-4923). Bethesda, MD: National Institute on Drug Abuse.
Kalin, N. H., Shelton, S., & Barksdale, C. (1988). Opiate modulation of separation-induced distress in non-human primates. Brain Research, 4401, 285292.
Kazdin, A. E. (1994). Informant variability in the assessment of childhood depression. In Reynolds, W. M. & Johnston, H. E. (Eds.), Handbook of depression in children and adolescents: Issues in clinical child psychology (pp. 249274). New York: Plenum Press.
Kennedy, S. E., Koeppe, R. A., Young, E. A., & Zubieta, J. K. (2006). Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Archives of General Psychiatry, 631, 11991208.
Kertes, D. A., Kalsi, G., Prescott, C. A., Kuo, P. H., Patterson, D. G., Walsh, D., et al. (2011). Neurotransmitter and neuromodulator genes associated with a history of depressive symptoms in individuals with alcohol dependence. Alcoholism: Clinical and Experimental Research, 351, 496505.
King, K. M., & Chassin, L. (2007). A prospective study of the effects of age of initiation of alcohol and drug use on young adult substance dependence. Journal of Studies on Alcohol and Drugs, 681, 256265.
Kleinjan, M., Poelen, E. A. P., Engels, R. C. M. E., & Verhagen, M. (2012). Dual growth of adolescent smoking and drinking: Evidence for an interaction between the mu-opioid receptor (OPRM1) A118G polymorphism and sex. Addiction Biology, 181, 10031012.
Kuntsche, E., Knibbe, R. A., Gmel, G., & Engels, R. C. M. E. (2005). Why do young people drink? A review of drinking motives. Clinical Psychology Review, 251, 841861.
Kuntsche, E., Knibbe, R. A., Gmel, G., & Engels, R. C. M. E. (2006). Who drinks and why? A review of socio-demographic, personality, and contextual issues behind the drinking motives in young people. Addictive Behaviors, 311, 18441857.
Lerman, C., Wileyto, E. P., Patterson, F., Rukstalis, M., Audrain-Mcgovern, J., Restine, S., et al. (2004). The functional mu-opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Pharmacogenomics Journal, 41, 184192.
Lewinsohn, P. M., Roberts, R. E., Seeley, J. R., Rohde, P., Gotlib, I. H., & Hops, H. (1994). Adolescent psychopathology: II. Psychosocial risk factors for depression. Journal of Abnormal Psychology, 1031, 302315.
Lopez-Duran, N. L., Kovacs, M., & George, C. J. (2009). Hypothalamic-pituitary-adrenal axis dysregulation in depressed children and adolescents: A meta-analysis. Psychoneuroendocrinology, 341, 12721283.
Marmorstein, N. R. (2009). Longitudinal associations between alcohol problems and depressive symptoms: Early adolescence through early adulthood. Alcoholism: Clinical and Experimental Research, 331, 4959.
McGee, R., Feehan, M., Williams, S., & Anderson, J. (1992). DSM-III disorders from age 11 to age 15 years. Journal of the American Academy of Child & Adolescent Psychiatry, 311, 5059.
Miller-Johnson, S., Lochman, J. E., Coie, J. D., Terry, R., & Hyman, C. (1998). Comorbidity of conduct and depressive disorders at sixth grade: Substance use outcomes across adolescence. Journal of Abnormal Child Psychology, 261, 221232.
Miranda, R., Ray, L., Justus, A., Meyerson, L. A., Knopik, V. S., McGeary, J., et al. (2010). Initial evidence of an association between OPRM1 and adolescent alcohol misuse. Alcoholism: Clinical and Experimental Research, 341, 112122.
Muthén, L. K., & Muthén, B. O. (1998–2007). Mplus: The comprehensive modeling program for applied researches. Los Angeles: Author.
Needham, B. L. (2007). Gender differences in trajectories of depressive symptomatology and substance use during the transition from adolescence to young adulthood. Social Science and Medicine, 651, 11661179.
Oroszi, G., Anton, R. F., O'Malley, S., Swift, R., Pettinati, H., Couper, D., et al. (2009). OPRM1 Asn40Asp predicts response to naltrexone treatment: A haplotype-based approach. Alcoholism: Clinical and Experimental Research, 331, 383393.
Pagan, J. L., Rose, R. J., Viken, R. J., Pulkkinen, L., Kaprio, J., & Dick, D. M. (2006). Genetic and environmental influences on stages of alcohol use across adolescence and into young adulthood. Behavior Genetics, 361, 483497.
Pardini, D., White, H. R., & Stouthamer-Loeber, M. (2007). Early adolescent psychopathology as a predictor of alcohol use disorders by young adulthood. Drug and Alcohol Dependence, 881(Suppl. 1), S38S49.
Parker, K. J., Schatzberg, A. F., & Lyons, D. M. (2003). Neuroendocrine aspects of hypercortisolism in major depression. Hormones and Behavior, 431, 6066.
Perlis, R. H., Fijal, B., Dharia, S., Heinloth, A. N., & Houston, J. P. (2010). Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biological Psychiatry, 671, 11101113.
Pieters, S., van der Vorst, H., Burk, W. J., Schoenmakers, T. M., Van den Wildenberg, E., Smeets, H. J., et al. (2011). The effect of the OPRM1 and DRD4 polymorphisms on the relation between attentional bias and alcohol use. Developmental Cognitive Neuroscience, 11, 591599.
Pieters, S., Van Der Zwaluw, C. S., Van Der Vorst, H., Wiers, R. W., Smeets, H., Lambrichs, E., et al. (2012). The moderating effect of alcohol-specific parental rule-setting on the relation between the dopamine D2 receptor gene (DRD2), the mu-opioid receptor gene (OPRM1) and alcohol use in young adolescents. Alcohol and Alcoholism, 471, 663670.
Poelen, E. A. P., Derks, E. M., Engels, R. C. M. E., Van Leeuwe, J. F. J., Scholte, R. H. J., Willemsen, G., et al. (2008). The relative contribution of genes and environment to alcohol use in early adolescents: Are similar factors related to initiation of alcohol use and frequency of drinking? Alcoholism: Clinical and Experimental Research, 321, 975982.
Poelen, E. A. P., Scholte, R. H. J., Engels, R. C. M. E., Boomsma, D. I., & Willemsen, G. (2005). Prevalence and trends of alcohol use and misuse among adolescents and young adults in the Netherlands from 1993 to 2000. Drug and Alcohol Dependence, 791, 413421.
Radloff, L. S. (1977). The CES-D Scale: A self-report depression scale for research in the general. Applied Psychological Measurement, 11, 385401.
Ray, L. A., & Hutchison, K. E. (2004). A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcoholism: Clinical and Experimental Research, 281, 17891795.
Ray, L. A., Miranda, R. Jr., Tidey, J. W., McGeary, J. E., MacKillop, J., Gwaltney, C. J., et al. (2010). Polymorphisms of the mu-opioid receptor and dopamine D4 receptor genes and subjective responses to alcohol in the natural environment. Journal of Abnormal Psychology, 1191, 115125.
Robinson, T. E., & Berridge, K. C. (2000). The psychology and neurobiology of addiction: An incentive-sensitization view. Addiction, 951, 91117.
Sander, T., Gsheidel, N., Wendel, B., Samochowiec, J., Smolka, M., Rommelspacher, H., et al. (1998). Human mu-opioid receptor variation and alcohol dependence. Alcoholism: Clinical and Experimental Research, 221, 21082110.
Saraceno, L., Munafó, M., Heron, J., Craddock, N., & van den Bree, M. B. (2009). Genetic and non-genetic influences on the development of co-occurring alcohol problem use and internalizing symptomatology in adolescence: A review. Addiction, 1041, 11001121.
Satorra, A., & Bentler, P. M. (2001). A scaled difference chi-square test statistic for moment structure analysis. Psychometrika, 661, 507514.
Schinka, J. A., Town, T., Abdullah, L., Crawford, F. C., Ordorica, P. I., Francis, E., et al. (2002). A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances. Molecular Psychiatry, 71, 224228.
Skitch, S. A., & Abela, J. R. (2008). Rumination in response to stress as a common vulnerability factor to depression and substance misuse in adolescence. Journal of Abnormal Child Psychology, 361, 10291045.
Sullivan, P. F., Neale, M. C., & Kendler, K. S. (2000). Genetic epidemiology of major depression: Review and meta-analysis. American Journal of Psychiatry, 1571, 15521562.
Tambs, K., Harris, J. R., & Magnus, P. (1997). Genetic and environmental contributions to the correlation between alcohol consumption and symptoms of anxiety and depression: Results from a bivariate analysis of Norwegian twin data. Behavior Genetics, 271, 241250.
Town, T., Abdullah, L., Crawford, F., Schinka, J., Ordorica, P. I., Francis, E., et al. (1999). Association of a functional mu-opioid receptor allele (+118A) with alcohol dependency. American Journal of Medical Genetics, 881, 458461.
Van der Zwaluw, C. S., & Engels, R. C. M. E. (2009). Gene–environment interactions and alcohol use and dependence: Current status and future challenges. Addiction, 1041, 907914.
Van der Zwaluw, C. S., Otten, R., Kleinjan, M., & Engels, R. C. (2013). Different trajectories of adolescent alcohol use: Testing gene–environment interactions. Alcoholism: Clinical and Experimental Research, 381, 704712.
Van Roekel, E., Engels, R. C. M. E., Verhagen, M., Goossens, L., & Scholte, R. H. (2011). Parental depressive feelings, parental support, and the serotonin transporter gene as predictors of adolescent depressive feelings: A latent growth curve analysis. Journal of Youth and Adolescence, 401, 453462.
Verdurmen, J., Monshouwer, K., van Dorsselaer, S., ter Bogt, T., & Vollebergh, W. (2005). Alcohol use and mental health in adolescents: Interactions with age and gender—Findings from the Dutch 2001 Health Behaviour in School-Aged Children Survey. Journal of Studies on Alcohol and Drugs, 661, 605609.
Zubieta, J. K., Ketter, T. A., Bueller, J. A., Xu, Y., Kilbourn, M. R., Young, E. A., et al. (2003). Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Archives of General Psychiatry, 601, 11451153.
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