Williams syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams syndrome is caused by a microdeletion of 26-28 genes on chromosome 7, including GTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias and language delay. Thus, genes in the region appear to regulate social motivation in a dose-sensitive manner. A "complete deletion" mouse, heterozygously eliminating the syntenic Williams syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role of Gtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressing Gtf2ird1, which can be used both to model duplication of this gene alone and to rescue Gtf2ird1 expression in the complete deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams syndrome critical region regulates social motivation along with motor and anxiety phenotypes, but that Gtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However, Gtf2ird1 complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

Adverse experiences superseding a child's capacity to sustain regulation of emotion and adaptive function are theorized to constitute "toxic stressors" when they induce a deleterious biological response within an individual. We ascertained presumptive parameters of toxic stress among 164 low-income infants and toddlers (ages 4-48 months) from 132 families enrolled in Early Head Start (EHS). We randomized a subset of these families into a pilot intervention arm of parenting education (the Incredible Years, TIY), which supplemented the EHS curriculum. Official report child abuse and neglect (CAN) and child behavior were serially ascertained over the course of the study. We observed relatively low associations among maternal depression, CAN, caregiver-child relationship quality, hair cortisol, and adverse child behavioral outcomes. Moreover, despite poverty and the high prevalence (51%) of CAN in this sample, the frequency of clinical-level internalizing and externalizing behavior among the children did not exceed that of the general population, by their parents' report. The pilot supplementation of EHS with TIY improved attendance in group meetings but did not significantly reduce adverse behavioral outcomes or CAN. This study revealed marked independence of standard indices of toxic stress (child maltreatment, maternal depression, caregiver emotional unavailability) which have been presumed to be risk factors for the development of psychopathology. That they were weakly inter-correlated, and only modestly predictive of child behavioral outcomes in this EHS sample, caution against presumptions about the toxicity of individual stressors, highlight the importance of ascertaining risk (and compensatory influences) comprehensively, suggest buffering effects of programs like EHS, and demonstrate the need for greater understanding of what parameterizes resilience in early childhood.

Background : Autism spectrum disorder (ASD) polygenic risk scores (PRS), derived from genome-wide association studies (GWAS), have been employed to predict ASD diagnosis in the general population ( Nagelkerke’s R 2 =2.45%). Critically, large genetic epidemiological studies have demonstrated that family members of affected individuals exhibit subclinical quantitative autistic traits (QAT), suggesting that diagnosed ASD is the pathological tail of a continuous distribution of QAT. Recent molecular genetic studies have reinforced these findings by uncovering a genetic correlation between ASD and QAT in the general population, emphasizing the importance of employing QAT in GWAS. Yet no study to date has examined the extent to which aggregated effects of common variants contributes to variance in QAT in a familial multiplex sample—one enriched for inherited ASD risk. Methods : Given the elevation of QAT among unaffected members in multiplex families, we examined the contribution of ASD-PRS to QAT, as measured by the Social Responsiveness Scale (SRS), in 1491 subjects from multiplex families in the Autism Genetic Resource Exchange (AGRE)—with (N=538) and without (N=921) an ASD diagnosis. Using the iPSYCH-ASD-GWAS as our discovery dataset, comprised of cases (N=8,605) and controls (N=19,526), we estimated how much variance in QAT that the ASD-PRS explained in our target dataset, AGRE. We also examined if there were interaction effects of diagnosis and sex. Results : The ASD-PRS explained 0.34% of the variance in QAT ( p =0.017). There was no significant interaction effect of disorder status ( p =0 . 511), but there was a significant interaction of sex ( p =0.027) and a significant interaction effect of ASD and sex ( p =0.031). Limitations : The primary limitation of this study is the small size of the discovery GWAS (iPSYCH). Conclusions: Our results reveal that autism-related polygenic load, as measured via the ASD-PRS, significantly predicts QAT—critically, in both affected and unaffected family members. Further, the association of ASD-PRS with QAT in females was modified by diagnosis, indicating that this relationship was the strongest among affected females.The unique nature of this study’s multiplex familial sample enables a novel demonstration that common polygenic variation in ASD contributes to familial QAT, particularly among affected females.

Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A “Complete Deletion” (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.

The relationship between risk and psychopathology in early childhood (EC), including the relative influence of genes and environment, are not well understood. Here we capitalized on data from 3 studies of infants and toddlers at risk to identify parameters of resilience that might be leveraged in efforts to support healthy EC development. The studies included: 1) a study of 164 children enrolled in Early Head Start, cross-referenced for official-report child maltreatment (CM), and prospectively followed for behavioral outcomes; 2) a toddler twin sample (n = 269 twin pairs) enriched for poverty and serially assessed for internalizing behavior; and 3) a sample of 225 consecutively enrolled newborns characterized for child abuse risk according to contemporary prediction algorithms, within an urban obstetrical service. First, we observed surprisingly low associations among CM, hypothalamic-pituitary-adrenal (HPA) axis variation, and maternal and child behavioral outcomes within the context of poverty, despite adequate statistical power to detect effects on both subclinical and clinical-level psychopathologic traits. Second, effects of poverty on internalizing behavior in EC were eclipsed by genetic factors, which were indexed in part by parental depression and substance use disorders. Finally, a program to provide resource navigation for preventive intervention was voluntarily accepted by mothers of at-risk newborns, 22% of whom had ≥50% risk for official-report CM by age 5 years, according to epidemiologic prediction algorithms. Acquisition of family mental health history and maternal history of childhood trauma comprised independent parameterizations of risk that stand to improve prediction algorithms for targeted preventive intervention. These findings underscore remarkable opportunities to leverage resilience in young children and their parents, particularly in the context of poverty. Our findings warrant caution against fatalistic presumptions about the deleteriousness of toxic stressors and inform refined strategies for implementing targeted preventive intervention.

ASD is characterized primarily by early-onset deficits in reciprocal social behavior (RSB). Autism-related variation in RSB (AVR) is highly heritable and continuously distributed in the general population, with ASD representing the pathological tail of that continuum. Although the lifelong stability of ASD has been established, the course of AVR across its entire range of variation has yet to be examined. Therefore, this cohort-sequential longitudinal study was undertaken to evaluate the stability of AVR over the course of childhood and early adulthood across the entire range of variation in which it manifests itself in nature.

Deficits in reciprocal social behavior are a characterizing feature of autism spectrum disorder (ASD). Autism‐related variation in reciprocal social behavior (AVR) in the general population is continuously distributed and highly heritable—a function of additive genetic influences that overlap substantially with those which engender clinical autistic syndromes. This is the first long‐term prospective study of the stability of AVR from childhood through early adulthood, conducted via serial ratings using the Social Responsiveness Scale, in a cohort‐sequential study involving children with ASD, other psychiatric conditions, and their siblings (N = 602, ages = 2.5–29). AVR exhibits marked stability throughout childhood in individuals with and without ASD.