Interacting effects of maternal responsiveness, infant regulatory problems and dopamine D4 receptor gene in the development of dysregulation during childhood: A longitudinal analysis
Introduction
Severe emotional and behavioral dysregulation in children and adolescents is a concept associated with both internalizing (anxious-depressed) and externalizing (disruptive) features. Dysregulation has recently been identified as a major risk for a variety of negative outcomes (Ayer et al., 2009, Biederman et al., 2009, Holtmann et al., 2011, Meyer et al., 2009). Problems with dysregulation are captured by a profile on the Child Behavior Checklist (Achenbach, 1991), the so called CBCL-dysregulation profile (CBCL-DP; Biederman et al., 2009, Holtmann et al., 2008) defined by peaks in the CBCL subdomains of attention, anxiety and aggressive behavior. This specific pattern of problems is suggested to be heritable (Hudziak et al., 2005) and quite stable throughout childhood (Althoff et al., 2006, Boomsma et al., 2006). Several studies have highlighted the significance of the CBCL-DP for psychopathology in demonstrating an increased risk for mood disorders, suicidality, substance abuse, personality disorders and disruptive behavior in affected children and adolescents (Ayer et al., 2009, Biederman et al., 2012, Holtmann et al., 2011, Meyer et al., 2009). In a cross-sectional study, Jucksch et al. (2011) found significant associations of the CBCL-DP with psychosocial adversities and impairment. Despite strong evidence for the prognostic and phenomenological value of the CBCL-DP, one major gap in current research is that there is hardly any information on early precursors or risk factors for the development of dysregulation. One of the few studies to date conducted in younger age groups (Kim et al., 2012) demonstrated that preschool children with the CBCL-DP displayed more negative temperament characteristics like high negativity and low effortful control and were exposed to more maladapted parenting compared to those without CBCL-DP. In a prospective, population-based study, Basten et al. (2013) found associations between dysregulation at age 5–7 years and higher levels of parental psychopathology and hostility at age 3 years, suggesting a strong role for parents' psychological problems and parenting style for the development of dysregulation in the offspring.
In general, parenting quality constitutes an important source of influence on behavioral outcome in their children. In particular, negative parenting including low responsiveness has been implicated in the later development of both externalizing and internalizing disorders (Campbell, 2002, Campbell et al., 2000, Laucht et al., 2001, Schmid et al., 2011). Maternal responsiveness, defined as the consistent and adequate response to infant's signals, is considered as a key parenting dimension that can serve as a powerful protective factor (Pasalich et al., 2011, Shaw et al., 2003). Moreover, evidence from recent research suggests that the association between rearing experiences and behavioral problems may be particularly pronounced in those children with adverse temperament characteristics. When exposed to negative, unresponsive or harsh parenting, so called “difficult” children were reported to be at risk for a broad range of behavior problems including disturbed self-regulation, conduct disorder, and aggressive behavior (Bates et al., 1998, Gilliom and Shaw, 2004, Kim and Kochanska, 2012, Lahey et al., 2008). Unresponsive parenting was shown to increase the risk for behavioral problems in temperamentally difficult children, while the risk was buffered in those children exposed to more responsive parenting (Kochanska and Kim, 2013). In this line, Keenan et al. (1998) suggested negative temperament traits to be the earliest measurable problem behavior in infants, with a high continuity to internalizing disorders in later life. The clinical classification system for infants (Zero to Three, DC 0–3R) subsumes these early observable, adverse temperament traits under the concept of regulatory problems (RP, Zero to Zero to Three, 2005). Infants with RP have difficulties with self-regulation and exhibit fussiness, irritability, poor self-calming or under-reactivity to stimuli as well as feeding and sleeping difficulties. In a recent meta-analysis, Hemmi et al. (2011) reported a strong association of RP in infancy with later externalizing and internalizing problems and ADHD, particularly in families with a high range of multiple risk factors. Schmid and Wolke (2014) suggested a cascade model in which early RP represent the starting point of a trajectory of dysregulation through time, with persistent RP indicating a “general dysregulation syndrome”.
Another powerful factor rendering children more or less vulnerable to their environment seems to be their genetic makeup (e.g., Caspi et al., 2002). Genetic variation in dopaminergic neurotransmission has been suggested to act as a susceptibility factor for behavior problems (Bakermans-Kranenburg and van Ijzendoorn, 2006, Bakermans-Kranenburg and van Ijzendoorn, 2007), implying a moderating effect of gene polymorphisms on the associations between rearing environments and developmental outcome. The DRD4 gene has been investigated specifically with regard to a wide range of issues associated with regulation problems, like ADHD and impulsivity (Congdon et al., 2008, Faraone et al., 2005, Swanson et al., 2000), infant temperament (De Luca et al., 2001), aggression (Benjamin et al., 2002, Schmidt et al., 2002) and self-regulation (Berry et al., 2014).
Located on chromosome 11p14, the DRD4 gene contains a variable number of tandem repeats (VNTR) polymorphism in exon 3. One allelic variant of this polymorphism, the exon 3 7-repeat (7r) allele, has been associated with lower dopamine reception efficiency and, in this line, with decreased attention and reward sensitivity (Robbins and Everitt, 1999), resulting in higher rates of mainly externalizing psychopathology during childhood. Investigating the joint contribution of DRD4 and environmental influences in the development of childhood behavioral problems, Bakermans-Kranenburg and van Ijzendoorn (2006) found carriers of the DRD4 7r allele to display greater levels of externalizing behaviors in preschool years when exposed to insensitive parenting compared to non-carriers (Bakermans-Kranenburg and van Ijzendoorn, 2006). In our own sample, results by Becker et al. (2010) demonstrated that variation in the DRD4 gene moderated the association of RP in infancy with later ADHD symptoms. According to these results, RP in infancy represented a risk factor for the development of ADHD later in life, but only if the genetic risk variant of DRD4 7r was present.
The majority of gene x environment (GxE) studies on children's genotypes and maternal responsiveness has been investigated using two-way interactions (see Kochanska et al., 2011). By contrast, studies involving two-way interactions which vary across levels of a third variable, like interactions between genotype, parental care and other factors with a proposed role in the development of later psychopathology are still rare in GxE research. However, recent studies suggest such complex patterns of interaction. For example, Cleveland et al. (2015) showed that a prevention program for alcohol use in adolescents reduced drinking risk, but only in DRD4 7r carriers with high levels of maternal involvement. Cicchetti et al. (2014) found that genetic variants associated with greater risk for borderline symptomatology after maltreatment experience were additionally moderated by gender, thus providing important implications for understanding variability in early predictors of psychopathology.
Following up our own findings on a cohort of children at risk (Becker et al., 2010, Becker et al., 2007, Holtmann et al., 2011, Laucht et al., 2001), we aimed to examine the complex interplay of maternal responsiveness, DRD4 gene and infant RP relating to later dysregulation in a prospective study since birth. We focused on maternal responsiveness, as this constitutes one of the most important factors in early self-regulation, with low responsiveness being associated with poor behavioral control in infancy (Cerezo et al., 2008). Based on the literature reviewed above, we hypothesized the presence of a three–way interaction, such that carriers of the DRD4 7r allele would show higher scores on the CBCL-DP during childhood, when exposed to low maternal responsiveness and that this effect would be more pronounced in children with RP than in those without.
Section snippets
Sample
Data were collected as part of the Mannheim Study of Children at Risk, a prospective longitudinal study from birth to adulthood. A total of 384 infants from the Rhine-Neckar region of Germany born between 1986 and 1988 were recruited. To be included in the study, parents and children had to meet well-defined criteria intended to enrich and control the risk status of the sample. Depending on pregnancy and birth history and on family background, children were assigned to one of nine subgroups of
Descriptive data
Correlations between predictors, covariates and CBCL-DP during childhood are presented in Table 2. DRD4 genotype was found to be unrelated to any of the other variables. RP were significantly associated with lower levels of infant responsiveness. While significantly linked with psychosocial adversity, the correlation of RP with childhood dysregulation just fell short of statistical significance. In addition, there was a positive relationship between maternal responsiveness and infant
Discussion
The present study demonstrated a moderating role for RP and DRD4 genotype in predicting the CBCL-DP from maternal responsiveness, indicating that in those DRD4 7r carriers with infant RP, lower maternal responsiveness was associated with increased scores on the CBCL-DP at age 8 and 11. In contrast, no significant effect of maternal responsiveness on later outcome was observed in non-carriers of the DRD4 7r allele irrespective of the presence of infant RP. As the CBCL-DP is composed of both
Conflict of interest
Luise Poustka received conference attendance support or was paid for public speaking by Lilly, Shire and Medice.
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
Contributors
Manfred Laucht, Tobias Banaschewski, Daniel Brandeis, Martin H. Schmidt and Günter Esser designed and supervised the study. Brigitte Schmid, Patricia Trautmann-Villalba, Katja Becker and Dorothea Blomeyer acquired the subjects and/or the data. Katrin Zohsel and Christine Jennen-Steinmetz undertook the statistical analysis. Luise Poustka and Katrin Zohsel interpreted the data and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Role of the funding source
Funding for this study was provided by the German Research Foundation (DFG). 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.
Acknowledgment
We thank Sibylle Heinzel and Elisabeth Reichert for their assistance in conducting the assessments.
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