Elsevier

Journal of Psychiatric Research

Volume 59, December 2014, Pages 53-59
Journal of Psychiatric Research

Are infants differentially sensitive to parenting? Early maternal care, DRD4 genotype and externalizing behavior during adolescence

https://doi.org/10.1016/j.jpsychires.2014.08.012Get rights and content

Abstract

Insensitive and unresponsive caregiving during infancy has been linked to externalizing behavior problems during childhood and adolescence. The 7-repeat (7r) allele of the dopamine D4 receptor (DRD4) gene has meta-analytically been associated with a heightened susceptibility to adverse as well as supportive environments. In the present study, we examined long-term effects of early maternal care, DRD4 genotype and the interaction thereof on externalizing and internalizing psychopathology during adolescence. As part of an ongoing epidemiological cohort study, early maternal care was assessed at child's age 3 months during a nursing and playing situation. In a sample of 296 offspring, externalizing and internalizing symptoms were assessed using a psychiatric interview conducted at age 15 years. Parents additionally filled out a questionnaire on their children's psychopathic behaviors. Results indicated that adolescents with the DRD4 7r allele who experienced less responsive and stimulating early maternal care exhibited more symptoms of ADHD and CD/ODD as well as higher levels of psychopathic behavior. In accordance with the hypothesis of differential susceptibility, 7r allele carriers showed fewer ADHD symptoms and lower levels of psychopathic behavior when exposed to especially beneficial early caregiving. In contrast, individuals without the DRD4 7r allele proved to be insensitive to the effects of early maternal care. This study replicates earlier findings with regard to an interaction between DRD4 genotype and early caregiving on externalizing behavior problems in preschoolers. It is the first one to imply continuity of this effect until adolescence.

Introduction

Externalizing behaviors in adolescents encompass disinhibited, undercontrolled and hostile behaviors such as aggression, impulsiveness, violence and delinquency. They constitute a major public health problem and are predictive of serious antisocial behavior, substance abuse and impaired physical health during adulthood (Fairchild et al., 2013, Odgers et al., 2008). Externalizing behaviors are commonly observed across a wide range of childhood disorders, especially in attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD) with or without accompanying callous-unemotional traits.

Several environmental factors have been discussed as being involved in the development of externalizing behaviors. Among these, harsh and inconsistent parenting as a response to children's misbehavior, promoting the development of coercive parent–child interactions (Jaffee et al., 2012), has been attributed a prominent role. However, parenting may be an important factor in the development of externalizing behaviors even earlier in life. During infancy, a caregiving environment characterized by parental insensitivity and low responsiveness has been consistently linked to avoidant and disorganized infant attachment patterns and subsequent externalizing behavior problems (Pasco Fearon and Belsky, 2011, van Ijzendoorn et al., 1999). This heightened risk for the development of externalizing behavior may be mediated by an inability of the child to develop a sense of self-confidence, generalized positive social expectations and effective emotion regulation (Fearon et al., 2010). Adverse effects of negative early caregiving on externalizing behavior have been proposed to be persistent or to even increase over the course of childhood (Fearon et al., 2010) and have been established until adolescence (Shaw et al., 2012).

Besides environmental factors, an individual's genetic makeup is assumed to be of relevance for the development of externalizing behavior. Family and twin-based heritability studies revealed a highly heritable vulnerability to externalizing behaviors (Rhee and Waldman, 2002, Tuvblad and Baker, 2011). In the attempt to elucidate the underlying molecular genetic basis, much research has focused on the dopaminergic neurotransmitter system (Pavlov et al., 2012), specifically the Dopamine D4 Receptor (DRD4) gene. The DRD4 gene on the long arm of chromosome 11 contains a highly polymorphic 48 base-pair variable number of tandem repeats (VNTR) sequence in exon III, which was found to vary between 2 and 11 copies, with the 4- and 7-repeat alleles (4r and 7r) being the most frequent (Lichter et al., 1993, Vallone et al., 2000). Consistent, albeit modest, associations have been reported between the DRD4 7r allele and ADHD (Gizer et al., 2009) and the presence of ODD among children with ADHD (Kirley et al., 2004).

Beyond genetic main effects, there is accumulating evidence that the DRD4 gene interacts with a variety of environmental influences to predict childhood externalizing behaviors (Bakermans-Kranenburg and van Ijzendoorn, 2011). With regard to early parenting, Bakermans-Kranenburg and van Ijzendoorn (2006) found that DRD4 7r carriers exposed to insensitive maternal care at 10 months of age showed significantly higher levels of externalizing behaviors when they were 3 years old. In contrast, in carriers of other DRD4 alleles, maternal insensitivity did not affect behavior. This effect seemed to be specific to externalizing behavior and was not observed for internalizing problems. Furthermore, children carrying the DRD4 7r allele were found to benefit most from a parent intervention program aimed at reducing externalizing behavior (Bakermans-Kranenburg et al., 2008). The latter findings, among others, suggest that carriers of the DRD4 7r allele may be characterized not by an elevated vulnerability to adverse environments only (diathesis-stress hypothesis) but rather by a heightened susceptibility to environmental influences in general (differential susceptibility hypothesis) (Belsky and Pluess, 2009).

To our knowledge, to date, no study has investigated whether and how the presence of the DRD4 7r allele moderates the effect of early maternal care on externalizing behavior later than early childhood. Hence, our present investigation aimed at examining the long-term effect of early maternal care, DRD4 genotype and the interaction thereof on externalizing behavior during adolescence. More specifically, the current study tested whether a potential gene-parenting interaction would be consistent with the hypothesis of diathesis-stress vs. differential susceptibility by applying the analysis of regions of significance (Kochanska et al., 2011, Roisman et al., 2012). According to the former model, adolescents carrying a genetic risk would exhibit higher levels of externalizing behavior when exposed to negative parenting, while they would be unaffected in positive rearing environments. In contrast, the latter model would predict that individuals with a high(er) genetic risk would respond more strongly to both environmental conditions, i.e., would exhibit higher levels of externalizing behaviors in negative environments and lower levels in positive environments. Moreover, to test the specificity of this effect, we included internalizing behavior problems as a concurrent outcome as well as psychosocial adversity as an additional environmental condition representing the larger social context.

Section snippets

Participants

The participants of the present evaluation were members of the Mannheim Study of Children at Risk, a prospective longitudinal study following infants at risk for later developmental disorders from birth to young adulthood. A total of 384 infants from the Rhine-Neckar region of Germany born between 1986 and 1988 were recruited consecutively according to a two-factorial design intended to enrich and control the risk status of the sample (Laucht et al., 2000, Laucht et al., 1997). One factor

Descriptive data

In Table 1, means and standard deviations of the main variables are presented for the total sample and, separately, by DRD4 genotype. Genotype groups did not differ significantly with regard to sex, psychosocial adversity, infant responsiveness or early maternal care.

Externalizing and internalizing psychopathology in adolescence

The findings of the linear regression analyses that tested the impact of DRD4 genotype, early maternal care and the interaction thereof on externalizing and internalizing symptoms in adolescence are summarized in Table 2.

Most

Discussion

In the study described here, we present longitudinal evidence for an interaction effect of early maternal care and DRD4 genotype on externalizing behavior during adolescence. Only in carriers of the DRD4 7r allele did a strong association between early maternal care and later externalizing behaviors emerge, with less stimulating and responsive caregiving resulting in more symptoms of ADHD and CD/ODD as well as psychopathic behaviors. Moreover, in this genotype group, high levels of maternal

Role of the funding source

Funding for this study was provided by the German Research Foundation (Deutsche Forschungsgemeinschaft) as part of the Special Research Program SFB 258 “Indicators and Risk Models of the Genesis and Course of Mental Disorders” at the University of Heidelberg, Germany. The funding source had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Manfred Laucht, Tobias Banaschewski, Daniel Brandeis, Manfred H. Schmidt and Günter Esser designed and supervised the study. Brigitte Schmid, Arlette F. Buchmann, Katja Becker and Dorothea Blomeyer acquired the subjects and/or the data. Katrin Zohsel and Christine Jennen-Steinmetz undertook the statistical analysis. Jörg Nikitopoulos and Katrin Zohsel interpreted the data and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

Jörg Nikitopoulos has received conference attendance support from Eli Lilly.

Tobias Banaschewski served in an advisory or consultancy role for Hexal Pharma, Lilly, Medice, Novartis, Otsuka, Oxford outcomes, PCM scientific, Shire and Viforpharma. He received conference attendance support and conference support or received speaker's fee by Lilly, Medice, Novartis and Shire. He is/has been involved in clinical trials conducted by Lilly, Shire & Viforpharma.

Katja Becker is/has been involved in

Acknowledgment

We thank Sibylle Heinzel and Elisabeth Reichert for their assistance in conducting the assessments.

References (52)

  • V. Asghari et al.

    Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants

    J Neurochem

    (1995)
  • M.J. Bakermans-Kranenburg et al.

    Gene-environment interaction of the dopamine D4 receptor (DRD4) and observed maternal insensitivity predicting externalizing behavior in preschoolers

    Dev Psychobiol

    (2006)
  • M.J. Bakermans-Kranenburg et al.

    Differential susceptibility to rearing environment depending on dopamine-related genes: new evidence and a meta-analysis

    Dev Psychopathol

    (2011)
  • M.J. Bakermans-Kranenburg et al.

    Experimental evidence for differential susceptibility: dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers' externalizing behavior in a randomized controlled trial

    Dev Psychol

    (2008)
  • J. Belsky et al.

    Beyond diathesis stress: differential susceptibility to environmental influences

    Psychol Bull

    (2009)
  • D. Berry et al.

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

    Dev Psychopathol

    (2013)
  • A.F. Buchmann et al.

    Interaction between prenatal stress and dopamine D4 receptor genotype in predicting aggression and cortisol levels in young adults

    Psychopharmacology (Berl)

    (2014)
  • J.W. Buckholtz et al.

    Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits

    Nat Neurosci

    (2010)
  • C. Delmo et al.

    Kiddie-SADS-Present and Lifetime version (K-SADS-PL) 3. Auflage der deutschen Forschungsversion

    (2000)
  • L.F. DiLalla et al.

    Genetic and gene-environment interaction effects on preschoolers' social behaviors

    Dev Psychobiol

    (2009)
  • J. Dmitrieva et al.

    Gender-specific expression of the DRD4 gene on adolescent delinquency, anger and thrill seeking

    Soc Cogn Affect Neurosci

    (2011)
  • B.J. Ellis et al.

    Differential susceptibility to the environment: an evolutionary–neurodevelopmental theory

    Dev Psychopathol

    (2011)
  • G. Fairchild et al.

    Research review: evaluating and reformulating the developmental taxonomic theory of antisocial behaviour

    J Child Psychol Psychiatry

    (2013)
  • R.P. Fearon et al.

    The significance of insecure attachment and disorganization in the development of children's externalizing behavior: a meta-analytic study

    Child Dev

    (2010)
  • P.J. Frick et al.

    Psychopathic traits and conduct problems in community and clinic-referred samples of children: further development of the psychopathy screening device

    Psychol Assess

    (2000)
  • P.J. Frick et al.

    The psychopathy screening device

    (1998)
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    Both authors contributed equally to this work.

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