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Gene–environment interaction between dopamine receptor D4 7-repeat polymorphism and early maternal sensitivity predicts inattention trajectories across middle childhood

Published online by Cambridge University Press:  30 April 2013

Daniel Berry
University of Illinois, Urbana–Champaign
Kirby Deater-Deckard
Virginia Polytechnic Institute and State University
Kathleen McCartney
Harvard University
Zhe Wang
Virginia Polytechnic Institute and State University
Stephen A. Petrill
Ohio State University
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Evidence suggests that the 7-repeat variant of a 48 base pair variable number tandem repeat polymorphism in the dopamine receptor D4 (DRD4) gene may be associated with the development of attention problems. A parallel literature suggests that genes linked to dopaminergic functioning may be associated with differential sensitivity to context, such that the direction of the genetic effect is hypothesized to vary across environmental experience. Guided by these literatures, we used data from the NICHD Study of Early Child Care and Youth Development to consider (a) whether individual differences in children's inattention problems across middle childhood are predicted by gene–environment interactions between the DRD4 gene 7-repeat polymorphism and children's experiences of maternal sensitivity across infancy and early childhood and (b) the degree to which such interactions are consistent with the differential-sensitivity model. Largely consistent with the hypothesized model, gene–environment interactions indicated that, in the context of insensitive early maternal care, the DRD4 7-repeat polymorphism was associated with higher levels of inattention. Although somewhat less consistently, there was also evidence that, in the context of highly sensitive care, the 7-repeat polymorphism was associated with lower levels of inattention. Overall, the magnitude of the absolute genetic effect increased over time, as children's inattention trajectories diverged.

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Achenbach, T. M. (1991). Integrative guide for the 1991 CBCL/4-18, YSR, and TRF profiles. Burlington, VT: University of Vermont, Department of Psychiatry.Google Scholar
Allison, P. D. (2003). Missing data techniques for structural equation modeling. Journal of Abnormal Psychology, 112, 545557.CrossRefGoogle ScholarPubMed
Anchordoquy, H. C. (2003). Genotyping of three candidate genes after whole-genome preamplification of DNA collected from buccal cells. Behavior Genetics, 33, 7378.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Bakermans-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.CrossRefGoogle ScholarPubMed
Bakermans-Kranenburg, M. J., van IJzendoorn, M. H., Pijlman, F. T., 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.CrossRefGoogle Scholar
Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2011). Differential susceptibility to rearing environment depending on dopamine-related genes: New evidence and a meta-analysis. Development and Psychopathology, 23, 3952.CrossRefGoogle Scholar
Barkley, R. A. (1997). Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD. Psychological Bulletin, 121, 6594.CrossRefGoogle ScholarPubMed
Belsky, J. (1997). Variation in susceptibility to rearing influences: An evolutionary argument. Psychological Inquiry, 8, 182186.CrossRefGoogle Scholar
Belsky, J., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2007). For better and for worse: Differential susceptibility to environmental influences. Current Directions in Psychological Science, 16, 300304.CrossRefGoogle Scholar
Belsky, J., Fearon, R. M. P., & Bell, B. (2007). Parenting, attention and externalizing problems: Testing mediation longitudinally, repeatedly and reciprocally. Journal of Child Psychology and Psychiatry and Allied Disciplines, 48, 12331242.CrossRefGoogle ScholarPubMed
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746754.CrossRefGoogle ScholarPubMed
Belsky, J., & Pluess, M. (2009). The nature (and nurture?) of plasticity in early human development. Perspectives in Psychological Science, 4, 345351.CrossRefGoogle ScholarPubMed
Berry, D., & Willett, J. B. (2009, April). Pre-kindergarten attention problems, teacher–child conflict, and achievement in late elementary school: A child-by-environment mediational growth model. Poster presented at the Biennial Conference of the Society for Research in Child Development Denver, CO.Google Scholar
Bollen, K. A., & Curran, P. J. (2005). Latent curve models: A structural equation perspective. New York: Wiley.CrossRefGoogle Scholar
Boyce, W. T., & Ellis, B. J. (2005). Biological sensitivity to context: I. An evolutionary–developmental theory of the origins and functions of stress reactivity. Development and Psychopathology, 17, 271301.CrossRefGoogle ScholarPubMed
Brock, L. L., Rimm-Kaufman, S. E., Nathanson, L., & Grimm, N. A. (2009). The contributions of “hot” and “cool” executive function to children's academic achievement, learning-related behaviors, and engagement in kindergarten. Early Research Quarterly, 24, 337349.CrossRefGoogle Scholar
Carey, W. B., & McDevitt, S. C. (1978). Revision of the infant temperament questionnaire. Pediatrics, 61, 735739.Google ScholarPubMed
Center for Disease Control and Prevention. (2005). Mental health in the United States: Prevalence of diagnosis and medication treatment for attention-deficit/hyperactivity disorder—United States, 2003. Morbidity and Mortality Weekly Report, 54, 842847.Google ScholarPubMed
Chang, F. M., Kidd, J. R., Livak, K. J., Pakstis, A. J., & Kidd, K. K. (1996). The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Human Genetics, 98, 91101.CrossRefGoogle Scholar
Collins, L. M., Schafer, J. L., & Kam, C. M. (2001). A comparison of inclusive and restrictive strategies in modern missing data procedures. Psychological Methods, 6, 330351.CrossRefGoogle Scholar
Costa, P. T., & McCrae, R. R. (1985). The NEO personality inventory manual. Odessa, FL: Psychological Assessment Resources.Google Scholar
Deater-Deckard, K., Petrill, S. A., Thompson, L., & DeThorne, L. (2005). A cross-sectional–behavioral genetic analysis of task persistence in the transition to middle childhood. Developmental Science, 8, F21F26.CrossRefGoogle ScholarPubMed
Duncan, G. J., Dowsett, C. J., Claessens, A., Magnuson, K., Huston, A. C., Klebanov, P., et al. (2007). School readiness and later achievement. Developmental Psychology, 43, 14281446.CrossRefGoogle ScholarPubMed
Dunn, L. M., & Dunn, L. M. (1981). Peabody Picture Vocabulary Test—Revised. Circle Pines, MN: American Guidance Service.Google Scholar
El-Faddagh, M., Laucht, M., Maras, A., Vöhringer, L., & Schmidt, M. H. (2004). Association of dopamine D4 receptor (DRD4) gene with attention-deficit/hyperactivity disorder (ADHD) in a high-risk community sample: A longitudinal study from birth to 11 years of age. Journal of Neural Transmission, 111, 883889.CrossRefGoogle Scholar
Faraone, S. V., Perlis, R. H., Doyle, A. E., Smoller, J. W., Goralnick, J. J., Holmgren, M. A., et al. (2005). Molecular genetics of attention-deficit/hyperactivity disorder. Biological Psychiatry, 57, 13131323.CrossRefGoogle ScholarPubMed
Fardo, D. W., Becker, K. D., Bertram, L., Tanzi, R. E., & Lange, C. (2009). Recovering unused information in genome-wide association studies: The benefit of analyzing SNPs out of Hardy–Weinberg equilibrium. European Journal of Human Genetics, 17, 16761682.CrossRefGoogle Scholar
Ficks, C. A., & Waldman, I. D. (2009). Gene–environment interactions in attention-deficit/hyperactivity disorder. Current Psychiatry Report, 11, 387392.CrossRefGoogle ScholarPubMed
Fleming, C. B., Harachi, T. W., Cortes, R. C., Abbott, R. D., & Catalano, R. F. (2004). Level and change in reading scores and attention problems during elementary school as predictors of problem behavior in middle school. Journal of Emotional and Behavioral Disorders, 12, 130144.CrossRefGoogle Scholar
Ford, D. H., & Lerner, R. M. (1992). Developmental systems theory: An integrative approach. Newbury Park, CA: Sage.Google Scholar
Freeman, B., Smith, N., Curtis, C., Huckett, L., Mill, J., & Craig, I. W. (2003). DNA from buccal swabs recruited by mail: Evaluation of storage effects on long-term stability and suitability for multiplex polymerase chain reaction genotyping. Behavior Genetics, 33, 6772.CrossRefGoogle ScholarPubMed
Friedman, N. P., Haberstick, B. C., Willcutt, E. G., Miyake, A., Young, S. E., Corley, R. P., et al. (2007). Greater attention problems during childhood predict poorer executive functioning in late adolescence. Psychological Science, 18, 893900.CrossRefGoogle ScholarPubMed
Gizer, I. R., Ficks, C., & Waldman, I. D. (2009). Candidate gene studies of ADHD: A meta-analytic review. Human Genetics, 126, 5190.CrossRefGoogle ScholarPubMed
Gottlieb, G. (1991). Experiential canalization of behavioral development: Theory. Developmental Psychology, 27, 413.CrossRefGoogle Scholar
Graham, J. W. (2003). Adding missing-data relevant variables to FIML-based structural equation models. Structural Equation Modeling: A Multidisciplinary Journal, 10, 80100.CrossRefGoogle Scholar
Gresham, F. M., & Elliott, S. N. (1990). The social skills rating system. Circle Pines, MN: American Guidance Service.Google Scholar
Hartl, D. L., & Clark, A. G. (1997). Principles of population genetics. Sunderland, MA: Sinauer Associates.Google Scholar
Hoza, B., Mrug, S., Gerdes, A. C., Hinshaw, S. P., Bukowski, W. M., Gold, J. A., et al. (2005). What aspects of peer relationships are impaired in children with ADHD? Journal of Consulting and Clinical Psychology, 73, 411423.CrossRefGoogle Scholar
Khan, S. A., & Faraone, S. V. (2006). The genetics of ADHD: A literature review of 2005. Current Psychiatry Reports, 8, 393397.CrossRefGoogle ScholarPubMed
Kim, J., Deater-Deckard, K., Mullineaux, P. Y., & Allen, B. (2010). Longitudinal studies of anger and attention span: Context and informant effects. Journal of Personality, 78, 419440.CrossRefGoogle ScholarPubMed
Kochanska, G., Murray, K. T., & Harlan, E. T. (2000). Effortful control in early childhood: Continuity and change, antecedents, and implications for social development. Developmental Psychology, 36, 220232.CrossRefGoogle ScholarPubMed
Kuntsi, J., Rijsdijk, F., Ronald, A., Asherson, P., & Plomin, R. (2005). Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood. Biological Psychiatry, 57, 647654.CrossRefGoogle ScholarPubMed
Levy, F., Hay, D. A., McStephen, M., Wood, C., & Waldman, I. D. (1997). Attention deficit hyperactivity disorder: A category or a continuum? Genetic analysis of a large-scale twin study. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 737744.CrossRefGoogle ScholarPubMed
Li, D., Sham, P. C., Owen, M. J., & He, L. (2006). Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder. Human Molecular Genetics, 15, 22762284.CrossRefGoogle ScholarPubMed
Li-Grining, C. P. (2007). Effortful control among low-income preschoolers in three cities: Stability, change, and individual differences. Developmental Psychology, 43, 208221.CrossRefGoogle ScholarPubMed
Magnusson, D. (1988). Individual development from an interactional perspective: A longitudinal study. Hillsdale, NJ: Erlbaum.Google Scholar
Masten, A. S., & Cicchetti, D. (2010). Developmental cascades. Development and Psychopathology, 22, 491495.CrossRefGoogle ScholarPubMed
McCartney, K., Harris, M. J., & Bernieri, E. (1990). Growing up and growing apart: A developmental meta-analysis of twin studies. Psychological Bulletin, 107, 226237.CrossRefGoogle ScholarPubMed
Meador-Woodruff, J. H., Damask, S. P., Wang, J., Haroutunian, V., Davis, K. L., & Watson, S. J. (1996). Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology, 15, 1729.CrossRefGoogle ScholarPubMed
Munafo, M. R., Yalcin, B., Willis-Owen, S. A., & Flint, J. (2008). Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: Meta-analysis and new data. Biological Psychiatry, 63, 197206.CrossRefGoogle ScholarPubMed
Murray-Close, D., Hoza, B., Hinshaw, S. P., Arnold, L. E., Swanson, J., Jensen, P. S., et al. (2010). Developmental processes in peer problems of children with attention-deficit/hyperactivity disorder in the Multimodal Treatment Study of Children With ADHD: Developmental cascades and vicious cycles. Development and Psychopathology, 22, 785802.CrossRefGoogle ScholarPubMed
Muthén, L. K., & Muthén, B. O. (2009). Mplus statistical analysis with latent variables: User's guide. Los Angeles: Author.Google Scholar
National Center for Early Development and Learning. (1997). Classroom Observation System–Kindergarten. Charlottesville, VA: University of Virginia Press.Google Scholar
NICHD Early Child Care Research Network. (1996). Characteristics of infant child care: Factors contributing to positive caregiving. Early Childhood Research Quarterly, 11, 296306.Google Scholar
NICHD Early Child Care Research Network. (1997). The effects of infant child care on infant–mother attachment security: Results of the NICHD Study of Early Child Care. Child Development, 68, 860879.Google Scholar
NICHD Early Child Care Research Network. (1999). Child care and mother–child interaction in the first three years of life. Developmental Psychology, 35, 13991413.CrossRefGoogle Scholar
NICHD Early Child Care Research Network. (2003). Do children's attention processes mediate the link between family predictors and school readiness? Developmental Psychology, 39, 581593.CrossRefGoogle ScholarPubMed
NICHD Early Child Care Research Network. (2009). Family–peer linkages: The mediational role of attentional processes. Social Development, 18, 875895.CrossRefGoogle Scholar
Oak, J. N., Oldenhof, J., & Van Tol, H. H. M. (2000). The dopamine D4 receptor: One decade of research. European Journal of Pharmacology, 405, 303327.CrossRefGoogle Scholar
Pelham, W. E., Gnagy, E., Greenslade, K. E., & Milich, R. (1992). Teacher ratings of DSM-III-R symptoms for the disruptive behavior disorders. Journal of the American Academy of Child & Adolescent Psychiatry, 31, 210218.CrossRefGoogle ScholarPubMed
Pope, A. W., Bierman, K. L., & Mumma, G. H. (1991). Aggression, hyperactivity and inattention–immaturity: Behavior dimensions associated with peer rejection in elementary school boys. Developmental Psychology, 27, 663671.CrossRefGoogle Scholar
Price, T. S., Simonoff, E., Asherson, P., Curran, S., Kuntsi, J., Waldman, I., et al. (2005). Continuity and change in preschool ADHD symptoms: Longitudinal genetic analysis with contrast effects. Behavior Genetics, 35, 121132.CrossRefGoogle ScholarPubMed
Radloff, L. S. (1977). The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measurement, 1, 385401.CrossRefGoogle Scholar
Raymond, M., & Rousset, F. (1995). GENEPOP (version 1.2): A population genetics software for exact test and ecumenicism. Journal of Heredity, 86, 248249.CrossRefGoogle Scholar
Rothbart, M. K., Ahadi, S. A., Hershey, K. L., & Fisher, P. (2001). Investigations of temperament at 3–7 years: The Children's Behavior Questionnaire. Child Development, 72, 13941408.CrossRefGoogle Scholar
Sameroff, A. J. (1983). Developmental systems: Contexts and evolution. In Mussen, P. H. (Series Ed.) & Kessen, W (Ed.), Handbook of child psychology: Vol. 1. History, theory, and methods (4th ed., pp. 237294). New York: Wiley.Google Scholar
Satorra, A., & Bentler, P. M. (2001). A scaled difference chi-square test statistic for moment structure analysis. Psychometrika, 66, 507514.CrossRefGoogle Scholar
Scarr, S. (1992). Developmental theories for the 1990s: Development and individual differences. Child Development, 63, 119.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Schoots, O., & Van Tol, H. H. M. (2003). The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics Journal, 3, 343348.CrossRefGoogle ScholarPubMed
Sheese, B. E., Voelker, P. M., Rothbart, M. K., & Posner, M. I. (2007). Parenting quality interacts with genetic variation in dopamine receptor D4 to influence temperament in early childhood. Development and Psychopathology, 19, 10391046.CrossRefGoogle ScholarPubMed
Thapar, A., Langley, K., Asherson, P., & Gill, M. (2007). Gene–environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective. British Journal of Psychiatry, 190, 13.CrossRefGoogle ScholarPubMed
Thapar, A., Langley, K., O'Donovan, M., & Owen, M. (2006). Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies. Molecular Psychiatry, 11, 714720.CrossRefGoogle ScholarPubMed
Willcutt, E. G., Doyle, A. E., Nigg, J. T., Faraone, S. V., & Pennington, B. F. (2005). Validity of the executive function theory of attention deficit/hyperactivity disorder: A meta-analytic review. Biological Psychiatry, 57, 13361346.CrossRefGoogle ScholarPubMed
Winer, B. J. (1971). Statistical principles in experimental design (2nd ed.). New York: McGraw–Hill.Google Scholar
Yong Zou, G., & Donner, A. (2006). The merits of testing Hardy–Weinberg equilibrium in the analysis of unmatched case-control data: A cautionary note. Annals of Human Genetics, 70, 923933.CrossRefGoogle Scholar

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Gene–environment interaction between dopamine receptor D4 7-repeat polymorphism and early maternal sensitivity predicts inattention trajectories across middle childhood
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