The Interactive Effects of Monoamine Oxidase A (MAOA) Gene and Peer Victimization on Depressive Symptoms in Early Adolescent Boys: The Moderating Role of Catechol-O-methyltransferase (COMT) Gene

CAO Cong1 WANG Meiping1 CAO Yanmiao1 JI Linqin1 ZHANG Wenxin1

(1.School of Psychology, Shandong Normal University, Jinan, China 250014)

【Abstract】The monoamine oxidase A (MAOA) gene, as an important candidate gene of depressive symptoms, has been demonstrated to interact with environmental factors, especially stressful life events and family environments, in predicting adolescent depressive symptoms. Peer victimization serves as a significant source of stress particularly during early adolescence and can lead to a series of psychosocial adjustment problems that even persist long after the experience of being harassed. However, it still remains unknown about whether or not the MAOA gene interacts with peer victimization on adolescent depressive symptoms. There is evidence about the significant interaction between the catechol-O-methyltransferase (COMT) gene and the MAOA gene on depressive symptoms. However, whether or not the COMT gene plays a moderating role on the interactive effects between MAOA gene and environmental factors is still unclear. Therefore, the present study aimed to examine (i) the interaction between the MAOA T94 G polymorphism and peer victimization on adolescent depressive symptoms and (ii) the moderating role of the COMT Val158 Met polymorphism in the aforementioned associations.The original participants (1440 adolescents, male = 757, 52.6%) were drawn from an ongoing longitudinal study, which recruiting children from 40 classes of 14 primary schools in Jinan, China. Because of the uncertain X-inactivation and resulting MAOA activity among females, this study limited our analyses on the male subsample. Using a 2-year longitudinal design, we first assessed adolescent depressive symptoms and peer victimization by self-rated Children’s Depression Inventory (CDI) and Peer Victimization Scale (PVS), respectively, at Time 1 (Mage= 11.32 years, SD = 0.49). At time 2 (Mage = 12.32 years, SD = 0.48), saliva samples of adolescents were collected and genotyped for the MAOA T941 and COMT Val158 Met polymorphisms using the Mass ARRAY Typer software version 3.4 (Sequenom), and the adolescent depressive symptoms were tested again using CDI. A series of hierarchical regressions were conducted to analyze the effects of genes and peer victimization on adolescent depressive symptoms. The results showed that, after depressive symptoms at Time 1 was controlled for, the MAOA T941 G polymorphism significantly interacted with peer victimization (i.e., physical victimization and relational victimization, respectively) in predicting depressive symptoms at Time 2. Among MAOA G allele carriers, the peer victimization positively predicted depressive symptoms; however, among MAOA T allele carriers, the peer victimization was not associated with depressive symptoms. More importantly, this interaction between the MAOA gene and the peer victimization was moderated by the COMT Val158 Met polymorphism, such that the aforementioned interaction only existed among COMT Met allele carriers, but not among Val/Val homozygotes. That is, among all the combined genotypes of the MAOA and COMT genes, only G-Met genotype carriers were susceptible to peer victimization. In summary, our results demonstrated that the peer victimization also served as an important candidate environmental factor and interacted with the MAOA gene in predicting depressive symptoms during early adolescence. Of particular note, such interactive effect between the MAOA gene and peer victimization was further moderated by the COMT Val158 Met polymorphism. These findings highlight the importance of investigating the moderating role of peer victimization in the association between genes and depressive symptoms during early adolescence. More importantly, this study underscores complex polygenic underpinnings of depressive symptoms and lends support for the multi-genes by environment interactions on the etiology of depressive symptoms.

【Keywords】 MAOA gene; COMT gene; peer victimization; depressive symptoms; multi-genes by environment interaction;

【Funds】 National Natural Science Foundation of China (31271105, 31671156) Specialized Research Fund for the Doctoral Program of Higher Education of China (20133704110001) Development Fund for the “Twelfth Five-year Plan” Key Disciplines (Developmental and Educational Psychology)

Download this article


    [1]. 1 Considering the nested structure in the sampling of this research, the zero-model of multilevel linear models (where no independent variables are inserted) was applied to examine the difference of adolescent depression in different classes at T1 (N = 2 199) and T2 (N = 2 157). The result showed that the intraclass correlation coefficients (icc) of the zero-model at T1 and T2 were 0.017 and 0.019, respectively. According to the multilevel correlation standards proposed by Cohen (1988), when the multilevel correlation was less than 0.059, the correlation was so small, indicating that a single-level model was likely to possess a relatively more stable standard error estimation, that the impact of the nested structure could be neglected. Thus, the subsequent data analysis applied the single-level model.

    [2]. 2 Factor synthesis method was applied to combine the educational background of parents, the employment of parents, and the monthly household income to get the social and economic family conditions (SES) score. The higher the score was, the better the SES was (Cao et al., 2016). According to the multilevel regression, after SES and depression at T1 were controlled, the interaction of the MAOA gene T941G polymorphism, the COMT gene VAL158Met polymorphism and the physical victimization still significantly estimated the adolescent depression at T2 (β = −0.24, t = −4.134, p < 0.001); only with the carriers of T941G G alleles and Val158Met Met alleles, physical victimization significantly and positively predicted adolescent depression at T2 (β = 0.21, t = 4.35, p < 0.001). Similarly, when SES and depression at T1 were controlled, the interaction of T941G, Val158Met polymorphism and relationship victimization was significant (β = −0.15, t = −2.73, p < 0.01); only the combination of T941G G alleles and Val158Met Met alleles was sensitive to relationship victimization (β = 0.19, t = 3.81, p < 0.001). This meant that when the controlled variable of SES was added, this research found that the interactive effect of G × G × E was still significant, and the significance was smaller than the threshold of multiple adjustments.


    Baker, M., Dorzab, J., Winokur, G., &Cadoret, R. (1972). Depressive disease:Evidence favoring polygenic inheritance based on an analysis of ancestral cases. Archives of General Psychiatry, 27, 320–327.

    Banny, A. M., Cicchetti, D., Rogosch, F. A., Oshri, A., &Crick, N. R. (2013). Vulnerability to depression:Amoderated mediation model of the roles of child maltreatment, peer victimization, and serotonin transporter linked polymorphic region genetic variation among children from low socioeconomic status backgrounds. Development and Psychopathology, 25, 599–614.

    Beach, S. R. H., Brody, G. H., Gunter, T. D., Packer, H., Wernett, P., &Philibert, R. A. (2010). Child maltreatment moderates the association of MAOA with symptoms of depression and antisocial personality disorder. Journal of Family Psychology, 24, 12–20.

    Belsky, J. &Beaver, K. M. (2011). Cumulative-genetic plasticity, parenting and adolescent self-regulation. Journal of Child Psychology and Psychiatry, 52, 619–626.

    Benjamin, D., van Bakel, I., &Craig, I. W. (2000). A novel expression based approach for assessing the inactivation status of human X-linked genes. European Journal of Human Genetics, 8, 103–108.

    Benjamini, Y., &Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B(Methodological), 57, 289–300.

    Benjet, C., Thompson, R. J., &Gotlib, I. H. (2010). 5-HTTLPR moderates the effect of relational peer victimization on depressive symptoms in adolescent girls. Journal of Child Psychology and Psychiatry, 51, 173–179.

    Cao, C., Chen, G. H., Wang, M. P., Cao, Y. M., &Zhang, W. X. (2014). Association between MAOA gene and depression. Advances in Psychological Science, 22, 1899–1910 (in Chinese).

    Cao, C., Wang, M. P., Ji, L. Q., Wei, X., Cao, Y. M., &Zhang, W. X. (2016). The MAOA rs6323 polymorphism interacts with maternal supportive parenting in predicting adolescent depression:Testing the diathesis-stress and differential susceptibility hypotheses. Acta Psychologica Sinica, 48, 22–35 (in Chinese).

    Carrel, L., &Willard, H. F. (2005). X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature, 434, 400–404.

    Caspi, A., Mc Clay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., ... Poulton, R. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851–854.

    Chen, J., Li, X., &Mc Gue, M. (2012). Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression. Genes, Brain and Behavior, 11, 958–965.

    Cicchetti, D., Rogosch, F. A., &Sturge-Apple, M. L. (2007). Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms:Depressive symptomatology among adolescents from low socioeconomic status backgrounds. Development and Psychopathology, 19, 1161–1180.

    Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed. ). Hillsdale, NJ:Lawrence Erlbaum Associates.

    Comasco, E., Sylvén, S. M., Papadopoulos, F. C., SundströmPoromaa, I., Oreland, L., &Skalkidou, A. (2011). Postpartum depression symptoms:A case-control study on monoaminergic functional polymorphisms and environmental stressors. Psychiatric Genetics, 21, 19–28.

    Doornbos, B., Dijck–Brouwer, D. A. J., Kema, I. P., Tanke, M. A. C., van Goor, S. A., Muskiet, F. A. J., &Korf, J. (2009). The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33, 1250–1254.

    Drabant, E. M., Hariri, A. R., Meyer-Lindenberg, A., Munoz, K. E., Mattay, V. S., Kolachana, B. S., ... Weinberger, D. R. (2006). Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. Archives of General Psychiatry, 63, 1396–1406.

    Dunn, E. C., Brown, R. C., Dai, Y., Rosand, J., Nugent, N. R., Amstadter, A. B., &Smoller, J. W. (2015). Genetic determinants of depression:Recent findings and future directions. Harvard Review of Psychiatry, 23, 1–18.

    Dunn, E. C., Uddin, M., Subramanian, S. V., Smoller, J. W., Galea, S., &Koenen, K. C. (2011). Research Review: Gene-environment interaction research in youth depression-a systematic review with recommendations for future research. Journal of Child Psychology and Psychiatry, 52, 1223–1238.

    Eisenhofer, G., &Finberg, J. P. (1994). Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. Journal of Pharmacology and Experimental Therapeutics, 268, 1242–1251.

    Evans, M. G. (1985). A Monte Carlo study of the effects of correlated method variance in moderated multiple regression analysis. Organizational Behavior and Human Decision Processes, 36, 305–323.

    Felten, A., Montag, C., Markett, S., Walter, N. T., &Reuter, M. (2011). Genetically determined dopamine availability predicts disposition for depression. Brain and Behavior, 1, 109–118.

    Forbes, E. E., &Dahl, R. E. (2012). Research Review:Altered reward function in adolescent depression:What, when and how?. Journal of Child Psychology and Psychiatry, 53, 3–15.

    Gohier, B., Senior, C., Radua, J., El-Hage, W., Reichenberg, A., Proitsi, P., ... Surguladze, S. A. (2014). Genetic modulation of the response bias towards facial displays of anger and happiness. European Psychiatry, 29, 197–202.

    Gong, P. Y., Xi, S. M., Shen, G. M., Li, S., Zhang, P. Z., Cao, G. C., ... Ma, H. (2013). The effects of DBH, MAOA, and MAOB on attentional biases for facial expressions. Journal of Molecular Neuroscience, 49, 606–613.

    Gottfredson, N. C., Foshee, V. A., Ennett, S. T., Haberstick, B., &Smolen, A. (2015). Genetic heterogeneity in adolescents depressive symptoms in response to victimization. Journal of Clinical Child&Adolescent Psychology, 44, 762–774.

    Hawker, D. S. J., &Boulton, M. J. (2000). Twenty years research on peer victimization and psychosocial maladjustment: A meta-analytic review of cross-sectional studies. Journal of Child Psychology and Psychiatry, 41, 441–455.

    Hotamisligil, G. S., &Breakefield, X. O. (1991). Human monoamine oxidase A gene determines levels of enzyme activity. American Journal of Human Genetics, 49, 383–392.

    Jabbi, M., Kema, I. P., van der Pompe, G., te Meerman, G. J., Ormel, J., &den Boer, J. A. (2007). Catechol-omethyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response. Psychiatric Genetics, 17, 183–193.

    Januar, V., Saffery, R., &Ryan, J. (2015). Epigenetics and depressive disorders:A review of current progress and future directions. International Journal of Epidemiology, 44, 1364–1387.

    Ji, L. Q., Chen, L., Xu, F. Z., Zhao, S. Y., &Zhang, W. X. (2011). A longitudinal analysis of the association between peer victimization and patterns of psychosocial adjustment during middle and late childhood. Acta Psychologica Sinica, 43, 1151–1162 (in Chinese).

    Kovacs, M., &Staff, M. (2003). Children’s depression inventory(CDI):Technical manual update. North Tonawanda, NY, USA: Multi-Health Systems, Inc.

    Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y. M., Szumlanski, C. L., &Weinshilboum, R. M. (1996). Human catecholO-methyltransferase pharmacogenetics:Description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics and Genomics, 6, 243–250.

    La Fontana, K. M., &Cillessen, A. H. N. (2010). Developmental changes in the priority of perceived status in childhood and adolescence. Social Development, 19, 130–147.

    Lancaster, T. M., Linden, D. E., &Heerey, E. A. (2012). COMT val158met predicts reward responsiveness in humans. Genes, Brain and Behavior, 11, 986–992.

    Larson, C. L., Taubitz, L. E., &Robinson, J. S. (2010). MAOA T941G polymorphism and the time course of emotional recovery following unpleasant pictures. Psychophysiology, 47, 857–862.

    Mandelli, L., &Serretti, A. (2013). Gene environment interaction studies in depression and suicidal behavior:An update. Neuroscience&Biobehavioral Reviews, 37, 2375–2397.

    Mynard, H., &Joseph, S. (2000). Development of the multidimensional peer-victimization scale. Aggressive Behavior, 26, 169–178.

    Papaleo, F., Crawley, J. N., Song, J., Lipska, B. K., Pickel, J., Weinberger, D. R., &Chen, J. S. (2008). Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. The Journal of Neuroscience, 28, 8709–8723.

    Peyrot, W. J., Milaneschi, Y., Abdellaoui, A., Sullivan, P. F., Hottenga, J. J., Boomsma, D. I., &Penninx, B. W. J. H. (2014). Effect of polygenic risk scores on depression in childhood trauma. The British Journal of Psychiatry, 205, 113–119.

    Plomin, R. (2013). Child development and molecular genetics: 14 years later. Child Development, 84, 104–120.

    Proitsi, P., Lupton, M. K., Reeves, S. J., Hamilton, G., Archer, N., Martin, B. M., ... Powell, J. F. (2012). Association of serotonin and dopamine gene pathways with behavioral subphenotypes in dementia. Neurobiology of Aging, 33, 791–803.

    Qian, Q. J., Yang, L., Wang, Y. F., Zhang, H. B., Guan, L. L., Chen, Y., ... Faraone, S. V. (2010). Gene-gene interaction between COMT and MAOA potentially predicts the intelligence of attention-deficit hyperactivity disorder boys in China. Behavior Genetics, 40, 357–365.

    Rice, F., Harold, G., &Thapar, A. (2002). The genetic aetiology of childhood depression: A review. Journal of Child Psychology and Psychiatry, 43, 65–79.

    Roy, M., Tapadia, M. G., Joshi, S., &Koch, B. (2014). Molecular and genetic basis of depression. Journal of Genetics, 93, 879–892.

    Rudolph, K. D., Troop-Gordon, W., Hessel, E. T., &Schmidt, J. D. (2011). A latent growth curve analysis of early and increasing peer victimization as predictors of mental health across elementary school. Journal of Clinical Child&Adolescent Psychology, 40, 111–122.

    Sugimura, N., &Rudolph, K. D. (2012). Temperamental differences in children’s reactions to peer victimization. Journal of Clinical Child&Adolescent Psychology, 41, 314–328.

    Troop-Gordon, W., Rudolph, K. D., Sugimura, N., &Little, T. D. (2015). Peer victimization in middle childhood impedes adaptive responses to stress:A pathway to depressive symptoms. Journal of Clinical Child&Adolescent Psychology44, 432–445.

    Wang, M. P., Ji, L. Q., &Zhang, W. X. (2015). Interaction effects between rs6323 polymorphism in the MAOA gene and peer relationship on early depression among male adolescents. Acta Psychologica Sinica, 47, 1260–1268 (in Chinese).

This Article


CN: 11-1911/B

Vol 49, No. 02, Pages 206-218

February 2017


Article Outline


  • 1 Problem statement
  • 2 Research method
  • 3 Results
  • 4 Discussion
  • 5 Conclusion
  • Footnote