A Role of Oxytocin Receptor Gene Brain Tissue Expression Quantitative Trait Locus rs237895 in the Intergenerational Transmission of the Effects of Maternal Childhood Maltreatment.

OBJECTIVE: Women exposed to childhood maltreatment (CM) are more likely to exhibit insensitive parenting, which may have consequences for their offspring's development. Variation in the oxytocin-receptor gene (OXTR) moderates risk of CM-associated long-term sequelae associated with mother-child attachment, although functionality of previously investigated single nucleotide polymorphisms (SNPs) remained elusive. Here, we investigated the role of OXTR rs237895, a brain tissue expression quantitative trait locus (eQTL), as a moderator of the relationship between CM and maternal behavior (MB) and the association between MB and offspring attachment security. METHOD: Of 110 women with information on rs237895 genotype (T-allele = 64, CC = 46), 107 had information on CM (CTQ) and 99 on standardized observer-based ratings of MB at 6 months postpartum (responsivity and detachment), which were used in principal component analysis to obtain a latent factor representing MB. Offspring (n = 86) attachment was evaluated at 12 months of age. Analyses predicting MB were adjusted for socioeconomic status, age, postpartum depression, and genotype-based ethnicity. Analyses predicting child attachment were adjusted for infant sex, socioeconomic status, and postpartum depression. RESULTS: rs237895 significantly moderated the relationship between CM and MB (F1;66 = 7.99, p < .01), indicating that CM was associated with maternal insensitivity only in high-OXTR-expressing T-allele carriers but not in low-OXTR-expressing CC homozygotes. Moreover, maternal insensitivity predicted offspring insecure attachment (B = -0.551; p < .05). CONCLUSION: Women with a high OXTR expressing genotype are more susceptible to CM-related impairments in MB that, in turn, predict attachment security in their children, supporting the role of the OT system in the intergenerational transmission of risk associated with maternal CM.

Course of Disinhibited Social Engagement Disorder From Early Childhood to Early Adolescence.

OBJECTIVE: Disinhibited social engagement disorder (DSED) is poorly understood beyond early childhood. The course of DSED signs in a sample of children who experienced severe, early deprivation from early childhood to early adolescence was examined using variable-centered (linear mixed modeling) and person-centered (growth mixture modeling) approaches. METHOD: The study included 124 children with a history of institutional care from a randomized controlled trial of foster care as an alternative to institutional care and 69 community comparison children matched by age and sex. DSED signs were assessed at baseline (mean age 22 months), 30, 42, and 54 months of age, and 8 and 12 years of age using a validated caregiver report of disturbed attachment behavior. RESULTS: Variable-centered analyses based on intent-to-treat groups indicated that signs of DSED decreased sharply for children randomized to foster care and decreased slightly but remained high for children randomized to care as usual. Person-centered analyses showed 4 profiles (i.e., elevated, persistent modest, early decreasing, and minimal). Elevated and persistent modest courses were associated with greater placement disruptions (F3,99 = 4.29, p = .007, partial eta-squared [η2] = 0.12), older age at placement into foster care (F3,56 = 3.41, p < .05, partial η2 = 0.16), and more time in institutional care (F3,115 = 11.91, p < .001, partial η2 = 0.24) compared with decreasing and minimal courses. CONCLUSION: Early and sustained placement into families after deprivation is associated with minimal or decreasing signs of DSED across development. Shortening the amount of time children spend in institutions and preserving placements could help decrease signs of DSED into early adolescence in previously institutionalized children.

Association between maternal childhood maltreatment and mother-infant attachment disorganization: Moderation by maternal oxytocin receptor gene and cortisol secretion.

This study examined maternal oxytocin receptor (OXTR, rs53576) genotype and cortisol secretion as moderators of the relation between maternal childhood maltreatment history and disorganized mother-infant attachment in the Strange Situation Procedure (SSP). A community sample of 314 mother-infant dyads completed the SSP at infant age 17 months. Self-reported maltreatment history more strongly predicted mother-infant attachment disorganization score and disorganized classification for mothers with more plasticity alleles of OXTR (G), relative to mothers with fewer plasticity alleles. Maltreatment history also more strongly predicted mother-infant attachment disorganization score and classification for mothers with higher SSP cortisol secretion, relative to mothers with lower SSP cortisol secretion. Findings indicate that maltreatment history is related to disorganization in the next generation, but that this relation depends on maternal genetic characteristics and cortisol.

The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age.

Disorganized attachment is an important early risk factor for socioemotional problems throughout childhood and into adulthood. Prevailing models of the etiology of disorganized attachment emphasize the role of highly dysfunctional parenting, to the exclusion of complex models examining the interplay of child and parental factors. Decades of research have established that extreme child birth weight may have long-term effects on developmental processes. These effects are typically negative, but this is not always the case. Recent studies have also identified the dopamine D4 receptor (DRD4) as a moderator of childrearing effects on the development of disorganized attachment. However, there are inconsistent findings concerning which variant of the polymorphism (seven-repeat long-form allele or non-seven-repeat short-form allele) is most likely to interact with caregiving in predicting disorganized versus organized attachment. In this study, we examined possible two- and three-way interactions and child DRD4 polymorphisms and birth weight and maternal caregiving at age 6 months in longitudinally predicting attachment disorganization at 36 months. Our sample is from the Maternal Adversity, Vulnerability and Neurodevelopment project, a sample of 650 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 was obtained with buccal swabs and categorized according to the presence of the putative allele seven repeat. Macroanalytic and microanalytic measures of maternal behavior were extracted from a videotaped session of 20 min of nonfeeding interaction followed by a 10-min divided attention maternal task at 6 months. Attachment was assessed at 36 months using the Strange Situation procedure, and categorized into disorganized attachment and others. The results indicated that a main effect for DRD4 and a two-way interaction of birth weight and 6-month maternal attention (frequency of maternal looking away behavior) and sensitivity predicted disorganized attachment in robust logistic regression models adjusted for social demographic covariates. Specifically, children in the midrange of birth weight were more likely to develop a disorganized attachment when exposed to less attentive maternal care. However, the association reversed with extreme birth weight (low and high). The DRD4 seven-repeat allele was associated with less disorganized attachment (protective), while non-seven-repeat children were more likely to be classified as disorganized attachment. The implications for understanding inconsistencies in the literature about which DRD4 genotype is the risk direction are also considered. Suggestions for intervention with families with infants at different levels of biological risk and caregiving risk are also discussed.

Modeling socially anhedonic syndromes: genetic and pharmacological manipulation of opioid neurotransmission in mice.

Social anhedonia, or the diminished capacity to experience pleasure and reward from social affiliation, is a major symptom of different psychiatric disorders, including some forms of infantile autism and schizophrenia spectrum disorders. The brain opioid hypothesis of social attachment is a promising model for achieving insights into how neurobiological and developmental factors contribute to the regulation of social reward. In this study, genetic knocking-out and naltrexone (NTRX) treatment during the first 4 days of life were used to disrupt opioid neurotransmission in mouse pups and their attachment relationships with the mother. Both permanent (genetic) and transient (pharmacological) manipulations of opioid neurotransmission exerted long-term effects on social affiliation. When juveniles, both µ-opioid receptor knockout mice and NTRX-treated pups showed reduced interest in peers and no preference for socially rewarding environment. These results demonstrate that sociability in juvenile mice is highly dependent on the establishment during infancy of a positive affective relationship with their mothers and that opioid neurotransmission has a major role in the regulation of social hedonic capacity. If the validity of this animal model will be confirmed by future research, translational studies focusing on the interaction between early experience and opioid neurotransmission could provide useful insights for identifying endophenotypes of human psychiatric disorders associated with social anhedonia.

Dopaminergic, serotonergic, and oxytonergic candidate genes associated with infant attachment security and disorganization? In search of main and interaction effects.

BACKGROUND AND METHODS: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems (DRD4, DRD2, COMT, 5-HTT, OXTR) on attachment security and disorganization. Parenting was assessed using observational rating scales for parental sensitivity (Ainsworth, Bell, & Stayton, 1974), and infant attachment was assessed with the Strange Situation Procedure. RESULTS: We found no consistent additive genetic associations for attachment security and attachment disorganization. However, specific tests revealed evidence for a codominant risk model for COMT Val158Met, consistent across both samples. Children with the Val/Met genotype showed higher disorganization scores (combined effect size d = .22, CI = .10-.34, p < .001). Gene-by-environment interaction effects were not replicable across the two samples. CONCLUSIONS: This unexpected finding might be explained by a broader range of plasticity in heterozygotes, which may increase susceptibility to environmental influences or to dysregulation of emotional arousal. This study is unique in combining the two largest attachment cohorts with molecular genetic and observed rearing environment data to date.

Genetic and environmental influence on attachment disorganization.

BACKGROUND: Empirical studies demonstrate that maternal sensitivity is associated with attachment security in infancy, while maternal frightening/frightened behavior is related to attachment disorganization. However, attachment disorganization is also predicted by individual dispositions in infancy. Indeed, recent studies indicate a link between attachment disorganization and DRD4 gene polymorphisms, thus suggesting a genetic vulnerability for attachment disorganization. The aims of our study were twofold, to test a) a possible direct link between molecular genetic variations and attachment disorganization, and b) a possible gene-environment interaction with a moderating effect of early maternal caregiving. METHODS: Attachment security and disorganization, as well as quality of maternal behavior were assessed in the infants of the Regensburg Longitudinal Study IV (N = 106) at the age of 12 months. DNA samples were collected in order to assess the exon III repeat polymorphism in the coding region and the -521 C/T single nucleotide polymorphism (SNP) in the regulatory region of the DRD4 gene and a repeat polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene. RESULTS: Significant associations were found between attachment disorganization and the short polymorphism of the serotonin transporter gene. Also, a gene-environment interaction indicated that this genetic association was only valid for infants of mothers exhibiting low responsiveness. No other significant genetic associations with attachment disorganization were apparent. CONCLUSIONS: The study suggests a gene-environment interaction whereby biological determinants of attachment disorganization are moderated by social experiences. Different pathways of the development of attachment disorganization are discussed based on a bio-behavioral model of development.

Association between the serotonin transporter promoter polymorphism (5-HTTLPR) and adult unresolved attachment.

Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This study examined the link between the 5-HTTLPR promoter polymorphism of the serotonin transporter gene and adult unresolved attachment assessed with the Adult Attachment Interview. Genetic material and information on attachment-related loss or trauma were available for 86 participants. Multivariate regression analyses showed an association between the short 5-HTTLPR allele and increased risk for unresolved attachment. Temperament traits and psychological symptoms did not affect the association between 5-HTTLPR and unresolved attachment. The authors hypothesize that the increased susceptibility to unresolved attachment among carriers of the short allele of 5-HTTLPR is consistent with the role of serotonin in modulation of frontal-amygdala circuitry. The findings challenge current thinking by demonstrating significant genetic influences on a phenomenon previously thought to be largely environmentally driven.

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

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 environmental 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 x 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.

Genetic, environmental and gender influences on attachment disorder behaviours.

BACKGROUND: Despite current interest in attachment disorder, there is concern about its discrimination from other disorders and an unproven assumption of an environmental aetiology. AIMS: To test whether behaviours suggestive of attachment disorder are distinct from other childhood behavioural and emotional problems and are solely environmentally determined. METHOD: In a community sample of 13,472 twins, we carried out factor analysis of questionnaire items encompassing behaviours indicative of attachment disorder, conduct problems, hyperactivity and emotional difficulties. We used behavioural genetic model-fitting analysis to explore the contribution of genes and environment. RESULTS: Factor analysis showed clear discrimination between behaviours suggestive of attachment disorder, conduct problems, hyperactivity and emotional problems. Behavioural genetics analysis suggested a strong genetic influence to attachment disorder behaviour, with males showing higher heritability. CONCLUSIONS: Behaviours suggestive of attachment disorder can be differentiated from common childhood emotional and behavioural problems and appear to be strongly genetically influenced, particularly in boys.

No association of the dopamine D4 receptor (DRD4) and -521 C/T promoter polymorphisms with infant attachment disorganization.

In a first molecular genetic study Lakatos and colleagues found an association between attachment disorganization and the dopamine D4 receptor (DRD4) gene polymorphism, in particular in the presence of the -521 T allele in the promoter region of the DRD4 gene. Replication of their study in a sample of 132 infants did not confirm the role of the DRD4 7+ -allele and the -521C/T promoter gene in disorganized attachment. Although our sample was larger, and contained more children with CT or TT alleles, which enhanced the probability of finding the DRD4 and C/T interaction, the association was not found. Even when we combined our sample with the Lakatos sample, the interaction effect of the DRD4 and -521 C/T polymorphisms on disorganized attachment was absent.

Attachment relationship experiences and childhood psychopathology.

Human infants form attachments to their caregivers gradually over the course of the first year of life. Qualitatively different types of attachments, which can be identified by the end of the first year, are broadly predictive of subsequent adaptive outcomes for young children. "Disorganized" patterns of attachment have the strongest links to concurrent and subsequent psychopathology, and considerable research has demonstrated both within-the-child and environmental correlates of disorganized attachment. Clinical disorders of attachment have been demonstrated to arise under conditions of social deprivation, such as institutionalization and maltreatment. An emotionally withdrawn/inhibited pattern and an indiscriminate/disinhibited pattern both have been described. Although these clinical types arise under similar conditions of environmental adversity, they tend to have different courses over time. We describe recent findings and highlight areas of emerging consensus and areas of continuing controversy regarding both disorganized patterns of attachment and clinical disorders of attachment in young children.

Dopamine D4 receptor (DRD4) gene polymorphism is associated with attachment disorganization in infants.

About 15% of one-year-old infants in non-clinical, low-risk and up to 80% in high-risk (eg maltreated) populations show extensive disorganized attachment behavior(1,2) in the Strange Situation Test.(3) It has also been reported that disorganization of early attachment is a major risk factor for the development of childhood behavior problems.(4) The collapse of organized attachment strategy has been explained primarily by inappropriate caregiving, but recently, the contribution of child factors such as neurological impairments and neonatal behavioral organization(6) has also been suggested. Here we report an association between the DRD4 III exon 48-bp repeat polymorphism and attachment disorganization. Attachment behavior of 90 infants was tested in the Strange Situation and they were independently genotyped for the number of the 48-bp repeats by polymerase chain reaction (PCR). The 7-repeat allele was represented with a significantly higher frequency in infants classified as disorganized compared to non-disorganized infants: 12 of 17 (71%) vs 21 of 73 (29%) had at least one 7-repeat allele (chi2 = 8.66, df = 1, P < 0.005). The estimated relative risk for disorganized attachment among children carrying the 7-repeat allele was 4.15. We suggest that, in non-clinical, low-social-risk populations, having a 7-repeat allele predisposes infants to attachment disorganization.