Gene-environment interactions across development: Exploring DRD2 genotype and prenatal smoking effects on self-regulation.

Developmental scientists (e.g. Bronfenbrenner & Ceci, 1994) have long emphasized that genetic and environmental influences mutually and dynamically interact to produce observable phenotypes. Only recently has it become possible to identify specific examples of gene-environment (GxE) interactions that are relevant to human psychological processes, typically by using the candidate gene approach (Caspi & Moffitt, 2006). Candidate gene designs involve comparison of groups of individuals with different alleles or forms of a gene. In a landmark study, Caspi and his colleagues (2002) found that individuals who had the monoamine oxidase A (MAOA) allele associated with higher activity and who had experienced substantial trauma in childhood were more likely to exhibit antisocial behavior. Since this landmark study, this GxE interaction has been replicated in several independent samples (e.g., Ducci et al., 2008; Widom & Brzustowicz, 2006) and has been extended to other outcomes such as depression (Cicchetti, Rogosch, & Sturge-Apple, 2007). GxE candidate gene studies have had a substantial impact in psychiatry in general, and in child psychiatry in particular, given the strong heritability of, and phenotypic variation within, many disorders. For example, the relation between insensitive parenting and externalizing behaviors in preschoolers varies by child genotype for the D4 dopamine receptor (DRD4; Bakermans-Kranenburg & Van Ijzendoorn, 2006). Only in preschool children with the DRD4 exon III 7-repeat allele was insensitive parenting associated with more frequent externalizing behaviors. Much work has been devoted to identifying continuity in key behaviors across developmental periods (Cote, Tremblay, & Nagin, 2002; Hill, Degnan, Calkins, & Keane, 2006). However, only a subset of children display such stability (Moffitt, 1993). It has been shown, for example, that the inattentive symptomatology that is central to ADHD diagnosis is not prominent in preschoolers, and for many children, manifests suddenly at school age (Lavigne, Arend, Rosenbaum, Binns, Christoffel, & Gibbons, 1998). Most adolescents “outgrow” hyperactivity and do not display such behaviors as adults (Mannuzza, Klein, Bessler, Malloy, & LaPadula, 1998). Although this different pattern is related in part to different age-based expectations for behavior (Wakschlag et al., 2007), little consideration has been given thus far to the possibility that interactive effects of genetics and the environment may vary across developmental periods. One environmental influence is maternal use of psychoactive substances during pregnancy. Smoking, drinking, illegal drug, and prescription drug use during pregnancy fundamentally alter the environment in which the fetus develops. Prenatal smoking, in particular, is associated with increased risk of childhood self-regulatory disorders (see Linnet et al., 2003, for a review), and there is some evidence that this risk may vary as a function of genetic factors. Neuman and colleagues (2007) found that, among children whose mothers reported cigarette smoking during pregnancy, the risk for diagnosis of attention deficit/hyperactivity disorder (ADHD) was highest in children with both the D4 dopamine receptor (DRD4) 7-repeat allele and the 3′variable number of tandem repeats (VNTR) 440 allele of the dopamine transporter (DAT1). Two other recent studies have identified gene by environment interactions involving the DAT1 candidate gene and prenatal tobacco exposure (PTE) in the etiology of externalizing behaviors (Becker, El-Faddagh, Schmidt, Esser, & Laught, 2008; Kahn, Khoury, Nichols, & Lanphear, 2003). Self-regulatory abilities are strongly implicated in ADHD (Nigg, 2005), and have a protracted course of development (Welsh, Pennington, & Groisser, 1991). Based on primate models, it has long been known the effects of lesions to the neural substrates of self-regulation differ depending on age (Goldman & Alexander, 1977). As such, examining the interactive effects of dopamine genotype and PTE at different points in development may be particularly fruitful in uncovering such patterns. We discuss the construct of self-regulation, its development, and the separate influences of PTE and another candidate gene involved in dopaminergic neurotransmission, the D2 dopamine receptor (DRD2). We then explore the effects of D2 genotype and PTE on self-regulation at two very different developmental periods, the neonatal and preschool, to illustrate the potential utility of this approach.