Journal of Child Psychology and Psychiatry 48:12 (2007), pp 1160–1173 doi:10.1111/j.1469-7610.2007.01801.x

Research Review: Genetic vulnerability or differential susceptibility in child development: the case of attachment

Marian J. Bakermans-Kranenburg and Marinus H. van IJzendoorn Centre for Child and Family Studies, Leiden University, The Netherlands

Gene–environment interactions interpreted in terms of differential susceptibility may play a large part in the explanation of individual differences in human development. Reviewing studies on the behavioral and molecular genetics of attachment, we present evidence for interactions between genetic and envir- onmental factors explaining individual differences in attachment security and disorganization. In particular, the DRD4 7-repeat polymorphism seems associated with an increased risk for disorganized attachment, but only when combined with environmental risk. Gene–environment (G · E) interactions may be interpreted as genetic vulnerability or differential susceptibility. We found support for the differential susceptibility hypothesis predicting not only more negative outcomes for susceptible children in unfavorable environments, but also positive outcomes for susceptible children in favorable environments. Keywords: Attachment, gene–environment interaction, differential susceptibility, disorganized attachment, dopamine, behavior problems, genetics.

Attachment theory is an important theoretical Hesse, 1999). Maternal sensitivity, however, framework for studying infant–parent relationships accounts for only a third of the association between and individual differences in emotion regulation. parental attachment representation and infant Attachment is the evolutionary-based, innate attachment security, leaving a transmission gap of predisposition of a child to seek proximity to and unexplained variance in infant attachment security contact with a specific figure, notably when the child (Van IJzendoorn, 1995; Belsky, 2005). Genetic is frightened, tired or ill (Bowlby, 1969/1982). In the factors affecting both security of attachment in the current review we take the development of attach- parent and in the offspring might bridge this gap. ment as an example to demonstrate the crucial role Whereas secure as well as insecure avoidant or of gene–environment interactions in explaining insecure ambivalent attachment relationships can individual developmental differences. We argue be considered organized strategies, adaptive to the that gene–environment interactions should not be child’s environment (Main, 1990) and speculated to restricted to negative environmental influences, enhance the child’s reproductive fitness (Belsky, emphasizing genetic vulnerabilities, but should be 1999), some attachment relationships are charac- interpreted in terms of differential susceptibility of terized by the (momentary) absence or breakdown of children to environmental influences, ‘for better or an otherwise organized strategy, hence defined as for worse’ (Belsky, 1997, 2005). disorganized (Main & Solomon, 1990; Hesse & Main, The idea that the environment plays a major part 2006). Indices of disorganized attachment behavior in explaining individual differences in quality of the are sequential or simultaneous display of contra- infant–parent attachment relationship is central to dictory behaviors, such as distress and avoidance, attachment theory (Ainsworth, Blehar, Waters, & undirected or misdirected movements and expres- Wall, 1978; Main, 1990). Parental sensitivity is sions, stereotypical and anomalous movements or generally regarded as the single most important postures, freezing or stilling behaviors, or expres- determinant of infant attachment security, particu- sions of fear or apprehension regarding the parent larly for the three organized attachment strategies: (Main & Solomon, 1990), which are unrelated to insecure-avoidant, secure, and insecure-ambivalent neurocognitive impairments in the child (Pipp- attachment (Ainsworth et al., 1978; Bretherton, Siegel, Siegel, & Dean, 1999). 1990; Pederson & Moran, 1995). Moreover, meta- The prevalence of attachment disorganization analytic results (Van IJzendoorn, 1995) demon- ranges from about 15% in normal, non-clinical strated that parents’ sensitivity to their children’s samples to 80% in maltreated samples (Carlson, attachment signals is partly determined by parents’ Cicchetti, Barnett, & Braunwald, 1989). Disorgan- own secure or insecure mental representation of ized attachment and sensitivity have been found to attachment as assessed with the Adult Attachment be only weakly associated, with a combined meta- Interview (AAI; Main, Kaplan, & Cassidy, 1985; analytic effect size of r ¼ .10 (Van IJzendoorn, Schuengel, & Bakermans-Kranenburg, 1999). But Conflict of interest statement: No conflicts declared. associations between specific environmental risk 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA Research Review: Genetic vulnerability or differential susceptibility in child development 1161 factors, including parental unresolved loss or and-pencil methods have been amazingly popular. trauma, and later infant disorganization have been The statistical need for relatively large samples has established in a number of studies (for a narrative probably hampered the application of behavioral review, see Lyons-Ruth & Jacobvitz, 1999; for a genetic methodologies in the field of attachment meta-analysis, see Van IJzendoorn et al., 1999). where detailed, labor-intensive observational Main and Hesse’s (1990) hypothesis of a link assessments prevail. Only a few studies on attach- between frightening or frightened parental behavior ment using genetically informative designs have and disorganized attachment has been tested and been conducted. Nevertheless, behavior genetic demonstrated (Abrams, Rifkin, & Hesse, 2006; methodologies can be viewed as useful natural Grienenberger, Kelly, & Slade, 2005; Jacobvitz, experiments (Rutter, 2003) to test developmental Leon, & Hazen, 2006; Schuengel, Bakermans- theories. Kranenburg, & Van IJzendoorn, 1999; True, Pisani, & Oumar, 2001). Lyons-Ruth, Bronfman, and Par- sons (1999) added extremely insensitive or disrupt- Behavioral genetics of attachment ive parental behaviors as potentially eliciting disorganization (see also Goldberg, Benoit, Blokland, Attachment of siblings and unrelated pairs. & Madigan, 2003; Madigan, Moran, & Pederson, Genetically informative studies include pairs of 2006b). children with divergent degrees of relatedness In a recent meta-analysis on the determinants of growing up in the same environment (or identical infant attachment disorganization, Madigan et al. twins growing up in different families). Attachment (2006a) found robust and moderate associations theory would suggest that children growing up in the between maternal unresolved loss or trauma, same family are likely to relate in similar ways to maternal frightening or anomalous behavior, and their parents, at least when parental attach- disorganized attachment in 12 studies including ment representations and interactive styles remain more than 800 families in total. However, less than stable across time. A study with biological siblings half of the association between unresolved loss/ (N ¼ 138 pairs) who were observed with their mother trauma and disorganized attachment was explained in the Strange Situation Procedure (SSP) when each by mediation of frightening parental behavior, and a sibling was between 12 and 14 months of age indeed second transmission gap has become apparent, showed significant concordance of attachment (62%; pointing to the need for further exploration of infant, 68% for siblings of the same gender; Van IJzendoorn parental, ecological, and genetic moderating and et al., 2000). Maternal insensitivity to both siblings mediating factors explaining disorganized attach- (shared environment) was associated with concor- ment. Genes seem plausible candidates for bridging dance of sibling non-security. the transmission gap because parents and infants In adoptive and step-families biologically unre- share 50% of their genes, and intergenerational lated siblings share the same caregiver, and any transmission of (disorganized) attachment may concordance in attachment quality is thus (partly) be based on transmission of genes from one accounted for by shared environmental influences. generation to the next. Unfortunately, no data on attachment for such families has become available yet. However, Sagi et al. (1995) reported on attachment of biologically unrelated ‘siblings’ in Israeli kibbutzim, where Behavioral genetics children typically spend much of their days with six Behavioral geneticists have stressed two major infants and two (biologically unrelated) caregivers in points: First, traditional research designs with one an ‘infant house’ from their third month onwards. child per family, focusing on between-family com- The classifications assigned to each pair of children parisons, may confound genetic similarities between observed with the same caregiver showed a concord- parents and children with supposedly shared envir- ance of 70% (n ¼ 27 pairs of children), suggesting onmental influences (Rowe, 1994; Plomin, 1994). that a substantial shared environmental component Second, talking about the influence of ‘the environ- accounted for the variance in attachment security. ment’ on child development confounds shared and The designs of these kibbutz and sibling studies unique environment. Indeed, behavioral genetic did not allow for distinguishing the role of (shared research on twins, siblings, and unrelated (adoptive and non-shared) environment from the role of genes, or step-)children have changed our views on child because of the absence of contrast groups with development drastically, and it has been argued that varying degrees of genetic relatedness. The question we have overestimated the role of parents in child of heritability of (disorganized) attachment could development (Harris, 1998; but see Collins, Mac- thus not be addressed. coby, Steinberg, Hetherington, & Bornstein, 2000; Rose, 1995). Attachment of twins. The first study of attachment Much of the behavioral genetic research involves of twins goes back to the early seventies (Brooks & large samples but meager measurements; paper- Lewis, 1974). Attachment behavior of 17 pairs of 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. 1162 Marian J. Bakermans-Kranenburg and Marinus H. van IJzendoorn opposite-sex twins was observed during 15 min of free Participants from two sites, London (United King- play of each of the twins with their mother. Proximity dom, 62 twin pairs) and Leiden (The Netherlands, 76 seeking, looking, touching, and pleasant vocal- twin pairs), were combined in Bokhorst et al.’s izations directed toward the mother were scored. (2003) study on attachment in twins. The two stud- Because the study focused on differences in attach- ies used similar designs and measures. For secure ment behaviors between boys and girls no associa- versus non-secure attachment as observed in the tions between pairs were reported. Moreover, since Strange Situation procedure 52% of the variance in only dizygotic (DZ) twins were included, any twin attachment security was explained by shared envir- concordance in attachment behavior could not be onment, and 48% of the variance was explained by compared to pairs with other degrees of relatedness. unique environmental factors and measurement In general, however, twin studies (including both error. The role of genetic factors was negligible. In the MZ and DZ twins) provide a unique opportunity to same study, genetic factors did explain 77% of the test the similarity of siblings’ attachment relation- variance in temperamental reactivity (and non- ships under conditions of similar age and child- shared environmental factors and measurement rearing contexts. Several studies on MZ and DZ error 23%), but differences in temperamental reac- twins’ attachment have been conducted, usually tivity were not associated with attachment concor- involving relatively small samples. Ricciuti (1992) dance. Similar results were shown for infant–father combined three small sample studies of twins attachment and temperamental dependency, both (Goldberg, Perrotta, Minde, & Corter, 1986, see also assessed with the Attachment Q-Sort (Vaughn & Minde, Corter, Goldberg, & Jeffers, 1990; Goldsmith Waters, 1990; Waters, 1995) in the Leiden part & Campos, 1990; Vandell, Owen, Wilson, & Hen- of this sample (Bakermans-Kranenburg, Van IJzen- derson, 1988). In this combined sample of 27 DZ doorn, Bokhorst, & Schuengel, 2004). Attachment twin pairs Ricciuti (1992) found 78% concordance of security was largely explained by shared environ- attachment security; concordance in the 29 MZ twin mental (59%) and unique environmental (41%) fac- pairs was 66%, and she therefore concluded that tors. For temperamental dependency, genetic factors attachment security did not show genetic influence. explained 66% of the variance, and non-shared Finkel, Wille, and Matheny (1998) found 67% environmental factors 34%. concordance of security in 34 MZ twins but only 38% Interestingly, disorganized attachment appears to concordance in 26 DZ twins, indicating only ‘modest behave differently when subjected to behavior- rearing environment effects’ (Finkel et al., 1998, genetic analysis. So far only one study (Bokhorst p. 7). It should be noted that the percentage of et al., 2003) has applied behavioral genetics to dis- DZ twin concordance is below chance (see Van organized attachment. Genetic modeling pointed to IJzendoorn et al., 2000). Finkel and Matheny (2000) only unique environmental factors explaining the reported on the complete Louisville Twin Study of variance in disorganization. attachment (including the 60 twin pairs from the It should be noted that twin studies of adult previous report). In 108 DZ twin pairs they found attachment representations and parental sensitivity only 48% concordance of attachment security, are lacking. Whether environmental influences are whereas in 99 MZ twin pairs 66% concordance was evident in measures of attachment in later childhood found. Finkel and her colleagues (1998, 2000) estim- and adulthood remains an important question to be ated the heritability of attachment at 25%; the addressed in future research. So far, genetic studies remaining variance was attributable to non-shared have only covered self-reported adult attachment environmental influences, without any role for styles (Brussoni, Jang, Livesley, & MacBeth, 2000; shared environmental influences. Finkel et al. (1998, Neyer, 2002) or self-reported parenting (Spinath & 2000), however, used a separation–reunion proced- O’Connor, 2003) – with diverse (and sometimes ure originally designed for assessing temperament, mixed) findings. Recently, the first study with AAIs and it should be noted that this adapted attachment conducted on twins has been reported (Constantino measure was only moderately associated with the et al., 2006), but genetic analyses were impossible Strange Situation procedure. since the design included only MZ twins (with and O’Connor and Croft (2001) observed 110 MZ and without conduct problems) reared together. Inter- DZ twin pairs at 43 months in the Strange Situation estingly, in a sample of genetically unrelated (adop- procedure. Attachment was coded using the pre- ted) sibling pairs (mean age 39 years), 61% school coding manual developed by Cassidy and concordance of AAI attachment security was found, Marvin in cooperation with the MacArthur Working suggesting that shared environment influences Group on Attachment (1992). Their findings sug- sibling similarities in attachment in adulthood gested a modest role for genetic influence (14%) and (Caspers, Yucuis, Troutman, Arndt, & Langbehn, in substantial influences of shared (32%) and non- press). shared (53%) environment. They did not find a The internal working models view of attachment mediating role for temperamental differences in would predict that continuity over time in patterns of explaining similarities or dissimilarities in attach- attachment would be driven by shared environ- ment between the siblings. mental factors (Fraley, 2002) – a prediction that

2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. Research Review: Genetic vulnerability or differential susceptibility in child development 1163 could be tested in longitudinal genetic studies of attachment classifications (regardless of their attachment. Several behavior geneticists have sug- zygosity). In that case the attachment classification gested that shared environmental factors are likely of each twin is equally well predicted from the to be more significant in infancy and early childhood sensitivity shown towards either twin, regardless of than later in life, and indeed genetic studies of genetic similarity. In contrast, when genetic factors individual differences in mental development and underlie the association between maternal sensit- temperament confirm this view (e.g., Plomin, 1994; ivity and attachment (sensitivity as experienced by Plomin & Daniels, 1987). Longitudinal genetic the child and attachment influenced by the same research would allow for the estimation of genetic genes), sensitivity expressed to one twin is a better and environmental influences at different develop- predictor of the other twin’s attachment classifica- mental stages and of their influence on age-to-age tion in MZ twins than in DZ twins. Finally, non- changes in attachment security. shared environmental factors are present when a parent’s sensitivity to one twin does not predict the other twin’s attachment security; in such cases strong within-twin correlations between sensitivity Shared and non-shared environment in and attachment are found but low cross-twin corre- attachment lations. Bivariate behavior genetic models use the What are these shared and non-shared environ- differences in within-twin and cross-twin correla- mental factors affecting infant attachment security, tions to estimate genetic, shared environmental and and what does the prominent role for unique non-shared environmental correlations between two environment in the case of disorganized attachment measures (Neale & Cardon, 1992; Plomin, DeFries, mean? For attachment security the importance of McClearn, & McGuffin, 2001; Purcell, 2001). shared environmental factors confirms one of the Fearon et al. (2006) found no evidence for a con- basic notions of attachment theory, and it may point tribution of genetic factors (residing in the infants) to to the vital importance of parental sensitivity. The differences in maternal sensitivity. The correlations question is whether parental sensitivity is shared or for sensitivity as rated from 1.5 hours of home non-shared across twins or siblings and, critically, observations by independent coders for twin 1 and whether sensitivity is associated with the shared or twin 2 were high in both MZ and DZ twins (between .64 non-shared aspects of attachment security. An and .69). Genetic modeling indicated that shared important weakness of univariate behavioral genetic environmental factors explained 66% of the variance studies such as described above is that they quantify in sensitivity as experienced by the child, and non- only the cumulative effects of a potentially large shared environmental factors 34%. Using bivariate number of unspecified processes (genetic or envir- behavior-genetic analyses it was then tested whether onmental). Since proposed mechanisms or estab- shared environmental and/or non-shared environ- lished correlates are not measured, it is difficult to mental processes were responsible for the link evaluate how behavior-genetic findings fit with between sensitivity and attachment (since there was empirical data on associations, and whether causal no genetic contribution to maternal sensitivity). interpretations of one kind or another are plausible. Shared environmental effects on sensitivity correlated The quantification of variance components is not with shared environmental effects on attachment informative about what specific factors actually play (rC ¼ .58), indicating that shared environmental a part (Deater-Deckard, 2000). In recent years there effects underlie the association between maternal has been increasing recognition of the limitations of sensitivity and attachment security, and that the univariate methods and the benefits of multivariate shared environmental component of maternal sensit- designs (e.g., Rutter, 2003). ivity accounted for approximately 33% of the corre- Using multivariate genetic analyses, Fearon et al. lation between twins in attachment security. (2006) included both maternal sensitivity and infant Non-shared environmental effects created an attachment of the Bokhorst et al. (2003) twin sam- inverse relationship between sensitivity and attach- ple, and examined the extent to which genetic and ment. This negative non-shared effect was small in environmental aspects of maternal sensitivity size, accounting for only 2% of the non-shared accounted for the pattern of similarity and dissimil- variance in attachment. What this implies is that arity in twins’ attachments to their mother. In non-shared environmental effects had the effect of theory, three factors might be responsible for the suppressing the phenotypic association resulting association between sensitivity and attachment. from the shared environmental pathway between First, the association between sensitivity and sensitivity and attachment. Greater sensitivity to one attachment may be attributed to shared environ- twin that was not expressed towards the other was mental factors. If maternal sensitivity is influenced associated with lower likelihood of security in the by her attachment representation and this in turn first twin. Or, alternatively, sensitivity towards twin causes variations in attachment security (Van IJz- 2 (that was not shown to twin 1) impacted positively endoorn, 1995), then consistencies in parenting on the twin 1’s attachment security. In short, shared behavior between twins lead to consistencies in their variance in maternal sensitivity accounted for part of 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. 1164 Marian J. Bakermans-Kranenburg and Marinus H. van IJzendoorn the similarity between twins in attachment security, Taken together, the influence of non-shared envir- but weak non-shared associations between sensit- onment is evident in organized and particularly in ivity and attachment suppressed the magnitude of disorganized attachment behavior. New ways of the correlation between attachment and sensitivity conceptualizing and investigating these non-shared in twin children. The attachment security of one twin influences are essential for the understanding of appears to depend on the relationship the parent has attachment processes. Their identification requires with the other twin. These findings underscore the valid measures of environmental factors, together importance of effects of relationships on relation- with designs that can separate genetic from envir- ships within a family system (Hinde & Stevenson- onmental influences. For disorganized attachment, Hinde, 1988). The identification of such non-shared the absence of any genetic effect might be somewhat influences is essential for the understanding of surprising given the molecular genetic findings of a attachment processes. Hungarian research group (see below), and given the For disorganized attachment, at least three factors idea that dissociation might be the underlying may contribute to the large effect of non-shared mechanism of disorganization (Hesse & Main, 2006). environment. First, in behavioral genetic modeling For dissociation some studies have reported a role non-shared environment cannot be distinguished for genetic factors (Becker-Blease et al., 2004; Jang from measurement error. The coding of attachment et al., 1998), although others did not (Waller & Ross, disorganization might be liable to intercoder differ- 1997; see also Harari, Van IJzendoorn, & Baker- ences and low reliability. It seems, however, unlikely mans-Kranenburg, 2007). that measurement error can account for a large part It should be noted that behavioral genetic studies of of the non-shared environmental factor, since the attachment used small samples and the confidence intercoder reliabilities in the pertinent studies were boundaries of the reported values for both genetic and adequate, and both statistically and theoretically environmental factors are broad; in the case of dis- significant associations have been reported across a organized attachment they are even based on only one substantial number of studies concerning the study. Furthermore, findings of behavioral genetic determinants and sequelae of disorganized attach- studies do not provide information about the relation ment (Van IJzendoorn et al., 1999). between actual genes and behavior. Gene expression Second, unique characteristics of the children that is not a straightforward process, and may be more are not shared by their (twin) siblings might be dependent on environmental influences than once responsible for the effect of non-shared environment. thought (e.g., Meaney, 2001; Meaney & Szyf, 2005; These unique child characteristics might either Rutter, 2006). Molecular genetic studies are a com- make the children differentially susceptible to plement – and sometimes an alternative – to behav- parenting influences (Belsky, 1997, 2005), or they ioral genetics. may evoke differential parenting. Bokhorst et al. (2003) reported that differences in observed fearful- ness, parent-reported temperament, and peri-natal Molecular genetics: the dopamine system conditions and experiences between the twins were not associated with differences in attachment dis- DRD4 and -521 C/T. In a first molecular genetic organization. Nevertheless, aspects of parenting that study on attachment Lakatos and colleagues (Laka- are experienced by one but not the other twin may tos et al., 2000) found an association between the have consequences for each of the twins’ attachment dopamine D4 receptor (DRD4) 7-repeat allele and as was shown in the Fearon et al. (2006) study. In a attachment disorganization. In previous studies the similar vein, attachment disorganization of one DRD4 gene polymorphism had shown associations twin may depend on the parenting behavior with pathological impulsive behavior and substance shown towards the other twin. Bivariate genetic abuse in adults and attention deficit hyperactivity studies of anomalous parenting and disorganized disorder (ADHD) in children. The dopaminergic attachment would be highly informative in this system is engaged in attentional, motivational, and regard. reward mechanisms (Robbins & Everitt, 1999), and Third, attachment disorganization may have vari- the 7-repeat allele has been linked to lower dopa- ous determinants, some of which may reside in the mine reception efficiency. In Lakatos’ (2000) low-risk unique environment (e.g., one twin sibling but not Hungary sample of 95 infants the estimated relative the other may have a near resemblance with a risk for disorganized attachment among children deceased relative, with unique consequences for carrying the 7-repeat allele was 4.15. There was no parental caregiving), others in the shared environ- association between the 7-repeat allele and the three ment (e.g., maternal depression, conflicts in the organized attachment classifications. marital relationship) or in genetic factors (see below). A second study with the same group of infants A large non-shared environmental effect may reflect involved additional analyses including the functional heterogeneity of the mechanisms leading to dis- -521 C/T single nucleotide polymorphism (Lakatos organized attachment, and maybe also heterogeneity et al., 2002). The -521 T variant has been shown to in the phenotype of disorganization. reduce transcriptional efficiency by approximately 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. Research Review: Genetic vulnerability or differential susceptibility in child development 1165

40% compared to the -521 C allele (Okuyama, 50 months of age. As described above, they had been Ishiguro, Toru, & Arinami, 1999), and may thus be observed with their mothers in the SSP at relevant for the dopaminergic neurotransmission. 13 months. The Leiden twins did not show an asso- Indeed the association between disorganized ciation of disorganized attachment with the 7-repeat attachment and the 7-repeat DRD4 allele was DRD4 allele (p ¼ .38), nor with the -521 C/T geno- stronger in the presence of the -521 T variant. In the type (p ¼ .20). The interaction was not significant presence of both the DRD4 7-repeat and the -521 T either (p ¼ .12). In the presence of the -521 T variant, allele in the upstream regulatory region of the DRD4 the 7-repeat DRD4 allele did not increase the risk for gene the risk for disorganized attachment was sug- attachment disorganization. Including one child of gested to increase tenfold (Lakatos et al., 2002). The each twin pair did not change the outcomes; the -521 C/T genotype itself had no effect on attachment Hungarian findings were not replicated. classification. No parental DNA was available for the Leiden A third study followed (Gervai et al., 2005). Using twins, and thus any disequilibrium in the trans- genetic data of the parents of the same sample of mission of the T.7 haplotype could not be tested. It infants as used in the previous two reports, the focus was, however, determined which children were carry- was now on the haplotype. Whereas in the Lakatos ing a T.7 haplotype and which children certainly et al. (2002) study the mere presence of both a DRD4 had no T.7 haplotype. Contrasting these children 7-repeat allele and a -521 T variant in the child’s (n ¼ 115) for attachment security and disorganiza- DNA had been associated with disorganized attach- tion no differences were found: secure attachment ment, parental DNA now provided the possibility to was evident in 58% of the children with the determine whether the presence of the T.7 haplotype T.7 haplotype and in 57% of the children without the (containing both DRD4 7-repeat allele and the -521 T T.7 haplotype, and disorganized attachment was variant) was responsible for attachment disorgan- observed in 23% of the children carrying the ization. Using transmission disequilibrium tests, it T.7 haplotype and in 19% of the children without the was tested whether heterozygous parents transmit- T.7 haplotype (Bakermans-Kranenburg & Van ted the T.7 haplotype at higher-than-chance rate to IJzendoorn, 2004). A second attempt to replicate disorganized infants. The frequencies of the haplo- Gervai et al.’s (2005) finding of an association types of the two polymorphisms (DRD4 7-repeat and between the presence or absence of the T.7 haplo- -521T) did not differ between parents of disorga- type and either attachment security or disorganiza- nized and parents of secure children, and a prefer- tion in a different sample also failed (Van IJzendoorn ential transmission of the 7-repeat allele from & Bakermans-Kranenburg, 2006). parents to disorganized children was not significant Further attempts followed. The appealing link (p ¼ .07). Parental genetic data, therefore, did not between DRD4 7-repeat and disorganized attachment confirm the link between the two polymorphisms has now been tested in six samples that we are aware and disorganized attachment. However, the absence of, some of them with unpublished data on this issue of the T.7 haplotype was related to secure attach- (the Hungarian sample, Lakatos et al., 2000, 2002; ment (p ¼ .01). Gervai et al., 2005; the Leiden and London twin samples, Bakermans-Kranenburg & Van IJzendoorn, Need for replication. Since multiple gene effects are 2004; Bokhorst et al., 2003; Fearon et al., 2006; the based on an increasingly large number of statistical Bielefeld study, Spangler & Zimmermann, 2007; the tests, and are thus liable to false positives (Ebstein, Leiden study on intergenerational transmission of Benjamin, & Belmaker, 2002), and the number of disorganized attachment, Schuengel et al., 1999; Van participants with particular genotype combinations IJzendoorn & Bakermans-Kranenburg, 2006; and the and the predicted phenotype becomes increasingly Leiden Longitudinal Study, Van der Mark, Van small (Van Gestel & Van Broekhoven, 2003), there IJzendoorn, & Bakermans-Kranenburg, 2002). The was a clear need for independent replication of the combined sample size of these studies amounts to study. Replication and – in a later stage – meta- 542 infant–mother dyads. Examining the association analyses are strongly recommended as strategies for between the presence of the DRD4 7-repeat allele rigorously testing the validity of reported gene to and disorganized attachment in this combined group behavior associations (e.g., Ioannidis, 2003). shows no significant effect, v2 (df ¼ 1, N ¼ 542) ¼ .29, Whereas a modest genetic effect would not be p ¼ .66. incompatible with an environmental explanation of Summarizing, we may say that the pioneering disorganized attachment (e.g., through differential study of the Hungarian group (Gervai et al., 2005; susceptibility; Belsky, 1997, 2005), a tenfold Lakatos et al., 2000, 2002) reported a potentially increase of the risk to become disorganized as the important role of two polymorphisms related to the result of two polymorphisms (Lakatos et al., 2002) is dopamine system, but independent replication of the stronger than the developmental model of disorgan- study did not confirm the role of the DRD4 7-repeat ized attachment would suggest. allele and the -521 C/T promoter gene in disorgan- In the Leiden twin sample (Bokhorst et al., 2003) ized attachment – although the power to find the cheek cells were collected from 132 children at tenfold increase in disorganized attachments in the

2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. 1166 Marian J. Bakermans-Kranenburg and Marinus H. van IJzendoorn attempted replication was more than 95% Caspi et al. (2002, 2003) for humans, an individual’s (Bakermans-Kranenburg & Van IJzendoorn, 2004). response to environmental influences may be mod- The combined effect size for the association erated by his or her genetic make-up (gene– between DRD4 and disorganized attachment is d ¼ environment interaction). Studies examining the .05. It should be noted that this is much smaller influence of (measured) gene by (measured) envir- than the combined effect size for the association onment (G · E) interactions illuminate how inherit- between anomalous parenting and disorganized ance contributes to both the dynamics and the attachment (Madigan et al., 2006b), which is d ¼ outcome of development (Michel & Moore, 1995; .72 (N ¼ 644). In previous studies the dopamine Moffitt, 2005; Moffitt, Caspi, & Rutter, 2005; Rutter, system has been associated with attention, state 2006; Rutter, Moffitt, & Caspi, 2006). A failure to regulation, and orienting responses in children, but include G · E interaction may lead to an overestima- also with alcohol and drug addiction in adults tion of the genetic component in the case of (Benjamin, Ebstein, & Belmaker, 2002; Ebstein an interaction between genes and shared environ- et al., 2002). Its influence on human functioning ment (Rutter, Pickles, Murray, & Eaves, 2001), and seems to be broad-band and rather non-specific. to an overestimation of the non-shared environ- State regulation and orientation to stimuli in the mental effects when actual interaction effects outside world may concern cognitive processes between genes and non-shared environment are not involved in the emergence of attachments – as well as taken into account (Eaves, Silberg, & Erkanli, 2003). in other aspects of socio-emotional development. If The finding that in the only genetically informative further research were to confirm that the dopamine study of attachment disorganization (Bokhorst et al., system is important for state regulation in infants, 2003) all variance was attributed to the non-shared infants with less adequate state regulatory abilities environmental component might reflect this omis- may have more problems with processing potentially sion of potential G · E effects. inconsistent and paradoxical communication from For disorganized attachment, the crucial question parents suffering from unresolved loss. However, the may be whether infants with the 7-repeat DRD4 scarce behavioural and genetic data are not allele are more susceptible to parental unresolved unequivocal. Spangler et al. (Spangler, Fremmer- loss and anomalous parenting behavior than infants Bombik & Grossmann, 1996; Spangler & Gross- without this allele. Recently, the first study com- mann, 1999) reported an association between bining molecular genetics with measurement of the attachment disorganization and lower newborn pertinent environmental influences on disorganized orienting ability and regulation. Somewhat para- attachment has been conducted (Van IJzendoorn & doxically, Ebstein et al. (1998) found the DRD4 Bakermans-Kranenburg, 2006). Unresolved loss or 7-repeat allele to be associated with better infant trauma as a distal index of a risk environment and orientation and state regulation. The latter results do frightening maternal behavior as a proximal risk not seem to support the idea that infants with the factor in the emergence of attachment disorganiza- 7-repeat DRD4 polymorphism were overrepresented tion were included. In a sample of 63 mothers who in Spangler et al.’s low-oriented newborns who were experienced at least one important loss (Schuengel later classified as disorganized. Now that genetic et al., 1999), unresolved loss was assessed with the data of Spangler et al.’s (1996) sample are available AAI. In the AAI (George, Kaplan, & Main, 1985; Main (Spangler & Zimmermann, 2007), it appears that the et al., 1985) the interviewee is asked about DRD4 7-repeat allele indeed did not play a role in childhood experiences and the influence of these explaining disorganized attachment in this sample. experiences, but also about any loss of loved ones and other traumatic experiences. Independent from secure or insecure mental representation of attach- ment, an unresolved classification is assigned if Gene–environment interaction lapses in the monitoring of reasoning or discourse In view of the behavioral genetic and molecular appear in the discussion of loss or trauma experi- studies on attachment, it must be concluded that the ences or if the participant describes extreme behav- empirical evidence to date falls short in explaining ioral reactions in connection with these experiences the presence or absence of secure and disorganized (Main & Goldwyn, 1984/1998). Frightening/fright- attachment behavior on the basis of mere genetic ened behavior (Main & Hesse, 1992/1995) of the factors. An alternative or complementary explana- mothers was coded on the basis of 3 to 4 hours of tion including genetic contributions to disorganized home observations when the infants were 10 to attachment pertains to the possibility of gene–envir- 11 months old. The Strange Situation procedure onment interaction, the interplay between ‘nature’ (Ainsworth et al., 1978) was administered between and ‘nurture’ deriving from genetic effects on liability 14 and 15 months. to risk exposure and susceptibility to environmental A moderating role of the DRD4 gene was found: risks (e.g., Bennett et al., 2002; Caspi et al., 2002, Maternal unresolved loss or trauma was associated 2003; Fox et al., 2005; Kaufman et al., 2004). As with infant disorganization, but only in the presence demonstrated by Suomi (1999) for primates and by of the DRD4 7-repeat allele in the child. Children 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. Research Review: Genetic vulnerability or differential susceptibility in child development 1167 with the short DRD4 allele did not show higher or by the idea of ‘genetic vulnerability’ (Paris, 2000; scores for disorganized attachment when their Rutter, 2006). The former idea implies that some mother was unresolved. The increase in risk for individuals, perhaps for genetic reasons, are more disorganization in children with the 7-repeat allele susceptible than others to positive as well as negat- exposed to maternal unresolved loss/trauma com- ive rearing experiences that influence both positive pared to children without these combined risks was and negative outcomes, whereas the latter model 18.8 fold. The T.7 haplotype showed a similar views some children as having a (genetic) suscept- interaction effect: an elevated risk for infant dis- ibility exclusively to a negative rearing experience organization in the case of maternal unresolved loss resulting in a negative outcome (see Figure 1). These (odds ratio 3.24). However, because children with two models are of course not mutually exclusive, but long DRD4 combined with -521 CC were absent in the differential susceptibility hypothesis predicts the sample the effects of the haplotype containing that not only will children who are more susceptible both the long DRD4 and the -521 T alleles could not to environmental influences show more negative be distinguished from the effects of DRD4 alone. For outcomes in unfavorable environments, but also that maternal frightening behaviour no moderating these children will show more positive outcomes effects were found. when they grow up in favorable environments. What do these findings imply? First, all particip- Although much of the biological processes involved ating mothers experienced the loss of a relative. The in these models are still unknown, changes in gene absence of an association between DRD4 7-repeat expression, known as environmental programming, and infant disorganization in this group of mothers may play a role (Meaney, 2001; Meaney & Szyf, means that the environmental risk of being exposed 2005). to a parent who suffered an important loss is insuf- Applied to the study of parental unresolved loss ficient for the child to become disorganized. As and infant disorganized attachment, the differential attachment theory would predict (Ainsworth & susceptibility hypothesis would predict higher levels Eichberg, 1991; Hesse, 1999; Hesse & Main, 2006), of disorganized attachment for infants with the long only parents who show signs of unresolved loss or DRD4 variants when their mothers struggle with trauma in their cognitive representation of past unresolved loss or other trauma, and lower levels of experiences might unwillingly stimulate their infants disorganization in children with the same genotype to become disorganized. Second, frightening paren- when their mothers do not show evidence of unre- tal behavior showed no moderating effect on infant solved loss. We tested this hypothesis empirically by disorganized attachment. The distal risk factor contrasting children with the long DRD4 variant of ‘unresolved loss’ must be transmitted to the child mothers without unresolved loss with the three other through some kind of parental behavior, but fright- groups. The contrast was significant; t (20.76, ening behavior might be just one of the possible unequal variances) ¼ 4.70 (p < .01). Children with pathways (and thus one of the relevant proximal risk long DRD4 who had mothers without unresolved factors), with others being important as well. loss showed significantly less attachment disorgan- Although the specific parental behavior that constit- ization than children with the short DRD4 variant utes the active ingredient of the environmental (regardless of their mothers’ unresolved loss component has yet to be revealed, the findings nicely status) or children with long DRD4 and mothers illustrate gene–environment interaction; they sup- with unresolved loss. The contrast with the latter port the idea that genetic effects may be contingent subgroup was also significant t (4.37, unequal vari- upon gene–environment co-action (Rutter, 2006). ances) ¼ 4.53 (p < .01), as was the contrast with the Research into gene–environment interactions, group of children with short DRD4 (regardless of complementary to the traditional environment- their mothers’ unresolved loss status), t (26.34, focused explanations of attachment, may be a fruitful approach to the understanding of the developmental pathways to (in-)secure and disorganized attach- ment. Extension of studies combining molecular genetics with careful measurement of environmental factors may provide the pathways to unraveling the interplay between genes and environment in the development of attachment relationships.

Towards a model for gene · environment interaction as differential susceptibility The search for gene–environment interactions may be inspired by the hypothesis of ‘differential sus- Figure 1 Genetic vulnerability and differential suscep- ceptibility’ (Belsky, 1997, 2005; Boyce & Ellis, 2005), tibility: a model 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. 1168 Marian J. Bakermans-Kranenburg and Marinus H. van IJzendoorn unequal variances) ¼ 3.19 (p < .01). These findings active gene–environment correlation as an alternat- support the notion that the DRD4 7-repeat allele ive explanation for the findings (see Kim-Cohen constitutes not only a genetic risk but may be a et al., 2006). genetic basis for differential susceptibility over the In order to test the ‘favorable side’ of the differen- whole range, with most positive outcomes for tial susceptibility hypothesis, we now contrasted children with the long DRD4 variant without the children with the long DRD4 polymorphism and negative environmental factor. sensitive mothers with the other groups. Indeed, Studies examining a negative outcome (disorgan- children with the DRD4 7-repeat polymorphism and ized attachment) and negative rearing environ- sensitive mothers tended to show the lowest levels ments (i.e., unresolved loss, frightening behavior) of externalizing problem behavior, t (43) ¼ 1.84, p ¼ may be considered only partially testing the differ- .07. A similar tendency was found for oppositional ential susceptibility hypothesis, because the behavior, t(43) ¼ 1.82, p ¼ .07; for aggressive absence of a negative outcome and a negative rearing behavior the contrast was significant, t(9.99, environment is not necessary equal to the presence unequal variances) ¼ 2.31, p ¼ .04, see Figure 2. of a positive rearing environment and positive Thus, children were differentially susceptible to both developmental outcomes. In this respect a crucial sensitive and insensitive parenting dependent on the question that remains to be addressed is whether the presence of the 7-repeat DRD4 allele. genotype that appears to make a child vulnerable to The next step in this line of research is testing unresolved loss vis-a`-vis disorganization also makes whether children with the DRD4 7-repeat allele are the organism more susceptible to certain positive differentially susceptible to experimental manipula- rearing experiences (e.g., high quality of sensitive tion of the environment. The findings of the first parenting) when it comes to a positive outcome (e.g., experimental tests of (measured) gene by (observed) higher levels of attachment security). environment interaction in human development In that regard one other study on differential indicate that children are indeed differentially sus- susceptibility and the role of DRD4 polymorphisms ceptible to intervention effects depending on genetic may be of interest. The study addressed not attach- differences. Children with the DRD4 7-repeat allele ment security or disorganization, but externalizing were more susceptible to experimentally induced problem behaviors (Bakermans-Kranenburg & Van changes in maternal discipline with respect to IJzendoorn, 2006). The 7-repeat DRD4 allele has externalizing behavior outcomes (Bakermans-Kran- been associated with several forms of (mal-)adjust- enburg, Van IJzendoorn, Pijlman, Mesman, & Juffer, ment in both childhood and adulthood, such as in press) and they showed lower levels of daily cor- aggression and other externalizing problems tisol (Bakermans-Kranenburg, Van IJzendoorn, in children (Benjamin et al., 2002; Schmidt, Fox, Mesman, Alink, & Juffer, in press) after an inter- Rubin, Hu, & Hamer, 2002). The role of harsh and vention aimed at enhancing maternal sensitivity and insensitive parenting in the development of positive discipline strategies (Van Zeijl et al., 2006). children’s aggressive and antisocial behaviors has These first studies testing the applicability of the also been amply documented (see Campbell, 2002), differential susceptibility hypothesis for positive but findings were not always convergent. The inter- environmental effects on the more susceptible play between DRD4 and observed parental insensit- groups involve relatively small samples and certainly ivity for externalizing problem behaviors (Child Behavior Checklist (CBCL); Achenbach, 1992) was tested in a sample of 47 twins, with a random 7 selection of one child per twin pair included in the No DRD4 7+ analyses (Bakermans-Kranenburg & Van IJzendo- 6 DRD4 7+ orn, 2006). A gene–environment interaction effect was found: Children with the 7-repeat DRD4 allele 5 and insensitive mothers displayed significantly more externalizing behaviors than children without the 4 DRD4 7-repeat allele (irrespective of maternal sensitivity). Maternal insensitivity was associated 3 with externalizing (oppositional, aggressive) behav- Aggression (CBCL) iors, but only in the presence of the DRD4 7-repeat polymorphism. The increase in externalizing behav- 2 iors in children with the 7-repeat allele exposed to insensitive care compared to children without these 1 combined risks was six fold. The results were repli- high sensitivity low sensitivity Parenting cated in the second half of the twin pair sample, with similar results (Bakermans-Kranenburg & Van Figure 2 Aggression (M,SE ) of children with and IJzendoorn, 2006). It should be noted that DRD4 without the DRD4 7-repeat allele experiencing sensitive was not related to maternal sensitivity, excluding or insensitive parenting 2007 The Authors Journal compilation 2007 Association for Child and Adolescent Mental Health. Research Review: Genetic vulnerability or differential susceptibility in child development 1169 need replication. Furthermore, future research may Correspondence to address the question whether such differential susceptibility to favorable and unfavorable environ- Marian J. Bakermans-Kranenburg and Marinus H. mental influences is also applicable to adult van IJzendoorn, Centre for Child and Family attachment and parenting behaviors. Parents with a Studies, Leiden University, P.O. Box 9555, 2300 RB DRD4 7-repeat allele may, for example, be more Leiden, The Netherlands; Tel +31 71 5273434; vulnerable to unresolved loss when they suffer the Fax +31 71 5273945; Email: bakermans@fsw. loss of a loved one or experience other traumatic leidenuniv.nl; [email protected] events, or their parenting may be more affected by the presence or absence of, e.g., a supportive partner relationship. References When these questions are addressed, it should be Abrams, K., Rifkin, A., & Hesse, E. (2006). Examining realized that genes steering the dopamine produc- the role of parental frightened/frightening subtypes tion are only one set of candidates to be investigated. in predicting disorganized attachment within a brief As an example of a polymorphism that affects the observation procedure. Development and Psycho- serotonin rather than the dopamine system, Caspi pathology, 18, 345–361. et al. (2003) found that negative life events predicted Achenbach, T.M. (1992). 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Marris (Eds.), Attachment across the life cycle (pp. Cadoret, & Philibert, 2003). 160–183). London: Routledge. Both serotonin and dopamine systems are highly Bakermans-Kranenburg, M.J., & Van IJzendoorn, M.H. relevant for attachment-related studies of the inter- (2004). No association of the dopamine d4 receptor play of genes and environment, because various (drd4) and -521 c/t promoter polymorphisms with investigations have documented the significance of infant attachment disorganization. Attachment and these systems for psychological functioning (e.g., Human Development, 6, 211–218. Bennett et al., 2002; Caspi et al., 2002, 2003; Fox Bakermans-Kranenburg, M.J., & Van IJzendoorn, M.H. (2006). Gene–environment interaction of the dopa- et al., 2005; Jaffee et al., 2005; Kaufman et al., mine d4 receptor (DRD4) and observed maternal 2004). 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