Skip to main content Accessibility help
×
×
Home

Evidence for a gene–gene interaction in predicting children's behavior problems: Association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds

  • Louis A. Schmidt (a1), Nathan A. Fox (a2) and Dean H. Hamer (a3)

Abstract

Recent work on the molecular genetics of complex traits in typical and atypical human development has focused primarilyon associations of single genes with behavior. Disparate literature suggests that the presence of one or two copies of the short allele of the serotonin transporter (5-HTT) gene and the long allele (7-repeat allele) version of the dopamine receptor D4 (DRD4) gene predicts internalizing- and externalizing-related behaviors, respectively. Apparently for the first time in the extant literature, we report a gene–gene statistical interaction on behavior problems in a group of typically developing children at age 7. DNA was extracted from buccal cells collected from 108 children and genotyped for short and long alleles of the 5-HTT gene and the short (2–5 repeats) versus long (6–8 repeats) allele of the DRD4 gene. Mothers completed the Child Behavior Checklist. As predicted, children with one or two copies of the short allele of the 5-HTT gene and the long allele version of the DRD4 gene exhibited significantly more internalizing and externalizing behaviors at age 7 than children with other combinations of the 5-HTT and DRD4 short and long genotypes. As well, children with the 5-HTT long and DRD4 long genotypes had the lowest reported scores on internalizing and externalizing behaviors at age 7, suggesting that the presence of the 5-HTT long genotype may serve as a protective factor against these behaviors in children with the long DRD4 genotype. Implications of these findings for understanding cumulative biological risk and protective factors in childhood behavior problems and psychopathology are discussed.

Copyright

Corresponding author

Address correspondence and reprint requests to: Louis A. Schmidt, Department of Psychology, Neuroscience and Behaviour, 1280 Main Street West, McMaster University, Hamilton, Ontario L8S 4K1, Canada; E-mail: schmidtl@mcmaster.ca.

References

Hide All
Achenbach, T. M. (1991). Manual for the Child Behavior Checklist/4-18 and 1991 profile. Burlington, VT: University of Vermont, Department of Psychiatry.
Achenbach, T. M., & Edelbrock, C. S. (1981). Behavioral problems and competencies reported by parents of normal and disturbed children aged four through sixteen. Monographs of the Society for Research in Child Development, 46(1, Serial No. 188), 182.
Asendorpf, J. B., & Meier, G. H. (1993). Personality effects on children's speech in everyday life: Sociability-mediated exposure and shyness-mediated reactivity to social situations. Journal of Personality and Social Psychology, 64, 10721083.
Auerbach, J. G., Benjamin, J., Faroy, M., Geller, V., & Ebstein, R. (2001). DRD4 related to infant attention and information processing: A developmental link to ADHD? Psychiatric Genetics, 11, 3135.
Bakerman-Kranenburg, M. J., & van IJzendoorn, M. H. (2006). Gene–environment interaction of the dopamine D4 receptor (DRD4) and observed maternal insensitivity predicting externalizing behavior in preschoolers. Developmental Psychobiology, 48, 406409.
Ball, D., Hill, L., Freeman, B., Eley, T. C., Strelau, J., Riemann, R., et al. (1997). The serotonin transporter gene and peer-related neuroticism. NeuroReport, 8, 13011304.
Benjamin, J., Ebstein, R. P., & Belmaker, R. H. (Eds.). (2002). Molecular genetics and the human personality. Washington, DC: American Psychiatric Association Press.
Benjamin, J., Li, L., Patterson, C., Greenberg, B. D., Murphy, D. L., & Hamer, D. H. (1996). Population and familial association between D4 dopamine receptor gene and measures of novelty seeking. Nature Genetics, 12, 8184.
Botto, L. D., & Mastroiacovo, P. (1998). Exploring gene–gene interactions in the etiology of neural tube defects. Clinical Genetics, 53, 456459.
Calkins, S. D., Fox, N. A., & Marshall, T. R. (1996). Behavioral and physiological antecedents of inhibited and uninhibited behavior. Child Development, 67, 523540.
Caspi, A., McClay, J., Moffitt, T. E., Mill, J., Martin, J., Craig, I. W., et al. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851854.
Caspi, A., & Moffitt, T. E. (2006). Gene–environment interactions in psychiatry: Joining forces with neuroscience. Nature Reviews Neuroscience, 7, 583590.
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HHT gene. Science, 301, 291293.
Cheek, J. M., & Buss, A. H. (1981). Shyness and sociability. Journal of Personality and Social Psychology, 41, 330339.
Cicchetti, D., & Blender, J. A. (2004). A multiple-levels-analysis approach to the study of developmental processes in maltreated children. Proceedings of the National Academy of Sciences of the USA, 101, 1732517326.
Cicchetti, D., & Blender, J. A. (2006). A multiple-levels-analysis perspective on resilience: Implications for the developing brain, neural plasticity, and preventive interventions. Annals of the New York Academy of Sciences, 1094, 248258.
Cloninger, C. R. (1987). A systematic method for clinical description and classification of personality variants. Archives of General Psychiatry, 44, 573588.
Cloninger, C. R., Adolfsson, R., & Svrakic, N. M. (1996). Mapping genes for human personality. Nature Genetics, 12, 34.
Curtis, W. J., & Cicchetti, D. (2007). Emotion and resilience: A multilevel investigation of hemispheric electroencephalogram asymmetry and emotion regulation in maltreated and nonmaltreated children. Development and Psychopathology, 19, 811840.
Deary, I. J., Battersby, S., Whiteman, M. C., Connor, J. M., Fowkes, F. G., & Harmar, A. (1999). Neuroticism and polymorphisms in the serotonin transporter gene. Psychological Medicine, 29, 735739.
DeYoung, C. G., Peterson, J. B., Seguin, J. R., Mejia, J. M., Pihl, R. O., Beitchman, J. H., et al. (2006). The dopamine D4 receptor gene and moderation of the association between externalizing behavior and IQ. Archives of General Psychiatry, 63, 14101416.
Ebstein, R. P., Levine, J., Geller, V., Auerbach, J., Gritsenko, I., & Belmaker, R. H. (1998). Dopamine D4 receptor and serotonin transporter promoter in the determination of neonatal temperament. Molecular Psychiatry, 3, 238246.
Ebstein, R. P., Nemanov, L., Klotz, I., Gritsenko, I., & Belmaker, R. H. (1997). Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III repeat polymorphism and the human personality trait of novelty seeking. Molecular Psychiatry, 2, 472477.
Ebstein, R. P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., et al. (1996). Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nature Genetics, 12, 7880.
Ebstein, R. P., Segman, R., Benjamin, J., Osher, Y., Nemanov, L., & Belmaker, R. H. (1997). 5-HT2C (HTR2C) serotonin receptor gene polymorphism associated with the human personality trait of reward dependence: Interaction with dopamine D4 receptor (D4DR) and dopamine D3 receptor (D3DR) polymorphisms. American Journal of Medical Genetics, 74, 6572.
Eley, T. C., Sugden, K., Corsico, A., Gregory, A. M., Sham, P., McGuffin, P., et al. (2004). Gene–environment interaction analysis of serotonin system markers with adolescent depression. Molecular Psychiatry, 9, 908915.
Fox, N. A. (1991). If it's not left, it's right: Electroencephalogram asymmetry and the development of emotion. American Psychologist, 46, 863872.
Fox, N. A. (1994). Dynamic cerebral processes underlying emotion regulation. Monographs of the Society for Research in Child Development, 59(2–3, Serial No. 240).
Fox, N. A., Calkins, S. D., & Bell, M. A. (1994). Neural plasticity and development in the first two years of life: Evidence from cognitive and socioemotional domains of research. Development and Psychopathology, 6, 677696.
Fox, N. A., Henderson, H. A., Rubin, K. H., Calkins, S. D., & Schmidt, L. A. (2001). Continuity and discontinuity of behavioral inhibition and exuberance: Psychophysiological and behavioral influences across the first four years of life. Child Development, 72, 121.
Fox, N. A., Nichols, K. E., Henderson, H. A., Rubin, K. H., Schmidt, L. A., Hamer, D., et al. (2005). Evidence for a gene–environment interaction in predicting behavioral inhibition in middle childhood. Psychological Science, 16, 921926.
Fox, N. A., Rubin, K. H., Calkins, S. D., Marshall, T. R., Coplan, R. J., Porges, S. W., et al. (1995). Frontal activation asymmetry and social competence at four years of age. Child Development, 66, 17701784.
Fox, N. A., Schmidt, L. A., Calkins, S. D., Rubin, K. H., & Coplan, R. J. (1996). The role of frontal activation in the regulation and dysregulation of social behavior during the preschool years. Development and Psychopathology, 8, 89102.
Gauderman, W. J. (2002). Sample size requirement for association studies of gene–gene interaction. American Journal of Epidemiology, 155, 478484.
Gelernter, J., Kranzler, H., Coccaro, E., Siever, L., New, A., & Mulgrew, C. L. (1997). D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects. American Journal of Human Genetics, 61, 11441152.
Goldman, D., Malhotra, A., Urbanek, M., Guenther, D., Robin, R., Virkkunen, M., et al. (1996). The dopamine DRD2 and DRD4 receptors: Lack of association to alcoholism, substance abuse and novelty seeking in Finnish Caucasians and Southwestern American Indians. Psychiatric Genetics Abstracts, 6, 162.
Gray, J. A. (1994). Three fundamental emotion systems. In Ekman, P. & Davidson, R. J. (Eds.), The nature of emotion: Fundamental questions (pp. 243247). New York: Oxford University Press.
Greenberg, B. D., Tolliver, T. J., Huang, S. J., Li, Q., Bengel, D., & Murphy, D. L. (1999). Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. American Journal of Medical Genetics, 88, 8387.
Hamer, D., & Copeland, P. (1998). Living with our genes. New York: Doubleday.
Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., et al. (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry, 66, 26212624.
Howard, T. D., Koppelman, G. H., Xu, J., Zheng, S. L., Postma, D. S., Meyers, D. A., et al. (2002). Gene–gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. American Journal of Human Genetics, 70, 230236.
Hunter, D. J. (2005). Gene–environment interactions in human diseases. Nature Reviews Genetics, 6, 287298.
Jonsson, E. G., Nothen, M. M., Gustavsson, J. P., Neidt, H., Brene, S., Tylec, A., et al. (1997). Lack of evidence for allelic association between personality traits and the dopamine D4 receptor gene polymorphisms. American Journal of Psychiatry, 154, 697699.
Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Grasso, D., Lipschitz, D., Houshyar, S., et al. (2006). Brain-derived neurotrophic factor–5-HTTLPR gene interactions and environmental modifiers of depression in children. Biological Psychiatry, 59, 673680.
Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Houshyar, S., Lipschitz, D., Krystal, J. H., et al. (2004). Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences of the USA, 1010, 1731617321.
Kendler, K. S., Kuhn, J. W., Vittum, J., Prescott, C. A., & Riley, B. (2005). The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: A replication. Archives of General Psychiatry, 62, 529535.
Kuhn, K. U., Meyer, K., Nothen, M. M., Gansicke, M., Papassotiropoulos, A., & Maier, W. (1999). Allelic variants of dopamine receptor D4 (DRD4) and serotonin receptor 5HT2C (HTR2C) and temperament: Replication tests. American Journal of Medical Genetics, 88, 168172.
Kumakiri, C., Kodama, K., Shimizu, E., Yamanouchi, N., Okada, S., Noda, S., et al. (1999). Study of the association between the serotonin transporter gene regulatory region polymorphism and personality traits in a Japanese population. Neuroscience Letter, 263, 205207.
LaHoste, G. J., Swanson, J. M., Wigal, S. B., Glabe, C., Wigal, T., King, N., et al. (1996). Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Molecular Psychiatry, 1, 121124.
Lappalainen, J., Zhang, L., Dean, M., Oz, M., Ozaki, N., Yu, D. H., et al. (1995). Identification, expression, and pharmacology of a cys(23)–ser(23) substitution in the human 5-HT2C receptor gene (HTR2C). Genomics, 27, 274279.
Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 15271531.
Lesch, K. P., Greenberg, B. D., Higley, J. D., Bennett, A., & Murphy, D. L. (2002). Serotonin transporter, personality, and behavior: Toward dissection of gene–gene and gene–environment interaction. In Benjamin, J., Ebstein, R. P., & Belmaker, R. H. (Eds.), Molecular genetics and the human personality (pp. 109135). Washington, DC: American Psychiatric Association Press.
Lichter, J. B., Barr, C. L., Kennedy, J. L., Van Tol, H. H., Kidd, K. K., & Livak, K. J. (1993). A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Human Molecular Genetics, 2, 767773.
Little, K. Y., McLaughlin, D. P., Zhang, L., Livermore, C. S., Dalack, G. W., McFinton, P. R., et al. (1998). Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. American Journal of Psychiatry, 155, 207213.
Malhotra, A. K., Virkkunen, M., Rooney, W., Eggert, M., Linnoilia, M., & Goldman, D. (1996). The association between the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and novelty seeking. Molecular Psychiatry, 1, 388391.
Mandelli, L., Serretti, A., Marion, E., Pirovano, A., Calati, R., & Colombo, C. (2007). Interaction between serotonin transporter gene, catechol-O-methyltransferase gene and stressful life events in mood disorders. International Journal of Neuropsychopharmacology, 10, 437447.
Moore, J. H., & Williams, S. M. (2002). New strategies for identifying gene–gene interactions in hypertension. Annals of Medicine, 34, 8895.
Negoro, K., McGovern, D. P. B., Kinouchi, Y., Takahashi, S., Lench, N. J., Shimosegawa, T., et al. (2003). Analysis of the IBD5 locus and potential gene–gene interactions in Crohn's disease. Gut, 52, 541546.
Noble, E. P., Ozkaragoz, T. Z., Ritchie, T. L., Zhang, X., Belin, T. R., & Sparkes, R. S. (1998). D2 and D4 dopamine receptor polymorphisms and personality. American Journal of Medical Genetics, 81, 257267.
Ono, Y., Manki, H., Yoshimura, K., Muramatsu, T., Mizushima, H., Higuchi, S., et al. (1997). Association between dopamine D4 receptor (D4DR) exon III polymorphism and novelty seeking in Japanese subjects. American Journal of Medical Genetics, 74, 501503.
Page, R. M. (1990). Shyness and sociability: A dangerous combination for illicit substance abuse in adolescent males? Adolescence, 25, 803806.
Plomin, R., & Rutter, M. (1998). Child development, molecular genetics, and what to do with genes once they are found. Child Development, 69, 12231242.
Pogue-Geile, M., Ferrell, R., Deka, R., Debski, T., & Manuck, S. (1998). Human novelty-seeking personality traits and dopamine D4 receptor polymorphisms: A twin and genetic association study. American Journal of Medical Genetics, 81, 4448.
Rutter, M., Moffitt, T. E., & Caspi, A. (2006). Gene–environment interplay and psychopathology: Multiple varieties but real effects. Journal of Child Psychology and Psychiatry, 47, 226261.
Sander, T., Harms, H., Dufeu, P., Kuhn, S., Rommelspacher, H., & Schmidt, L. G. (1997). Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics. American Journal of Medical Genetics, 74, 483487.
Santesso, D. L., Schmidt, L. A., & Fox, N. A. (2004). Are shyness and sociability still a dangerous combination for substance use? Evidence from a U.S. and Canadian sample. Personality and Individual Differences, 37, 517.
Schmidt, L. A. (1999). Frontal brain electrical activity in shyness and sociability. Psychological Science, 10, 316320.
Schmidt, L. A. (2003). Shyness and sociability: A dangerous combination for preschoolers. International Society for the Study of Behavioural Development Newsletter, 27, 68.
Schmidt, L. A., & Fox, N. A. (1999). Conceptual, biological, and behavioral distinctions among different categories of shy children. In Schmidt, L. A. & Schulkin, J. (Eds.), Extreme fear, shyness, and social phobia: Origins, biological mechanisms, and clinical outcomes (pp. 4766). New York: Oxford University Press.
Schmidt, L. A., & Fox, N. A. (2002). Molecular genetics of temperamental differences in children. In Benjamin, J., Ebstein, R. P., & Belmaker, R. H. (Eds.), Molecular genetics and the human personality (pp. 247257). Washington, DC: American Psychiatric Association Press.
Schmidt, L. A., Fox, N. A., Perez-Edgar, K., Hu, S., & Hamer, D. H. (2001). Association of DRD4 with attention problems in normal childhood development. Psychiatric Genetics, 11, 2529.
Schmidt, L. A., Fox, N. A., Rubin, K. H., Hu, S., & Hamer, D. H. (2002). Molecular genetics of shyness and aggression in preschoolers. Personality and Individual Differences, 33, 227238.
Segalowitz, S. J., & Schmidt, L. A. (in press). Capturing the dynamic endophenotype: A developmental psychophysiological manifesto. In Schmidt, L. A. & Segalowitz, S. J. (Eds.), Developmental psychophysiology: Theory, systems, and methods. Cambridge: Cambridge University Press.
Serretti, A., Mandelli, L., Lorenzi, C., Landoni, S., Calati, R., Insacco, C., et al. (2006). Temperament and character in mood disorders: Influence of DRD4, SERTPR, TPH and MAO-A polymorphisms. Neuropsychobiology, 53, 916.
Shiozawa, M., Provoost, A. P., Van Dokkum, R. P. E., Majewski, R. R., & Jacob, H. J. (2000). Evidence of gene–gene interactions in the genetic susceptibility to renal impairment after unilateral nephrectomy. American Society of Nephrology, 11, 20682078.
Strobel, A., Wehr, A., Michel, A., & Brocke, B. (1999). Association between the dopamine D4 receptor (DRD4) exon III polymorphism and measures of novelty seeking in a German population. Molecular Psychiatry, 4, 378384.
Sullivan, P. F., Fifield, W. J., Kennedy, M. A., Mulder, R. T. T., Sellman, J. D., & Joyce, P. R. (1998). No association between novelty seeking and the type 4 dopamine receptor gene (DRD4) in two New Zealand samples. American Journal of Psychiatry, 155, 98101.
Swanson, J. M., Sunohara, G. A., Kennedy, J. L., Regino, R., Fineberg, E., Wigal, T., et al. (1998). Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): A family-based approach. Molecular Psychiatry, 3, 3841.
Tomitaka, M., Tomitaka, S., Otuka, Y., Kim, K., Matuki, H., Sakamoto, K., et al. (1999). Association between novelty seeking and dopamine receptor D4 (DRD4) exon III polymorphism in Japanese subjects. American Journal of Medical Genetics, 88, 469471.
Van Boven, H. H., Vandenbroucke, J. P., Briet, E., & Rosendaal, F. R. (1999). Gene–gene and gene–environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood, 94, 25902594.
Vandenbergh, D. J., Zonderman, A. B., Wang, J., Uhl, G. R. & Costa, P. T. Jr. (1997). No association between novelty seeking and dopamine D4 receptor (D4DR) exon III seven repeat alleles in Baltimore Longitudinal Study of Aging participants. Molecular Psychiatry, 2, 417419.
Westernberg, H. G., Murphy, D. L., & Den Boer, J. A. (Eds.). (1996). Advances in the neurobiology of anxiety disorders. New York: Wiley.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Development and Psychopathology
  • ISSN: 0954-5794
  • EISSN: 1469-2198
  • URL: /core/journals/development-and-psychopathology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

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