Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland.

BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).

Altered Thalamocortical Connectivity in 6-Week-Old Infants at High Familial Risk for Autism Spectrum Disorder.

Converging evidence from neuroimaging studies has revealed altered connectivity in cortical-subcortical networks in youth and adults with autism spectrum disorder (ASD). Comparatively little is known about the development of cortical-subcortical connectivity in infancy, before the emergence of overt ASD symptomatology. Here, we examined early functional and structural connectivity of thalamocortical networks in infants at high familial risk for ASD (HR) and low-risk controls (LR). Resting-state functional connectivity and diffusion tensor imaging data were acquired in 52 6-week-old infants. Functional connectivity was examined between 6 cortical seeds-prefrontal, motor, somatosensory, temporal, parietal, and occipital regions-and bilateral thalamus. We found significant thalamic-prefrontal underconnectivity, as well as thalamic-occipital and thalamic-motor overconnectivity in HR infants, relative to LR infants. Subsequent structural connectivity analyses also revealed atypical white matter integrity in thalamic-occipital tracts in HR infants, compared with LR infants. Notably, aberrant connectivity indices at 6 weeks predicted atypical social development between 9 and 36 months of age, as assessed with eye-tracking and diagnostic measures. These findings indicate that thalamocortical connectivity is disrupted at both the functional and structural level in HR infants as early as 6 weeks of age, providing a possible early marker of risk for ASD.

De novo homozygous variant of the SCN1A gene in a patient with severe Dravet syndrome complicated by acute encephalopathy.

Variants in the SCN1A gene have been identified in epilepsy patients with widely variable phenotypes and they are generally heterozygous. Here, we report a homozygous missense variant, NM_001165963.4: c.4319C>T (p.Ala1440Val), in the SCN1A gene which seemed to occur de novo together with a gene conversion event. It's highly possible that this variant, although located in a critical functional domain of protein Nav1.1, depending on the nature of the amino acid substitution, may not cause the complete loss of protein function. And the accumulated effect by having this variant on both alleles results in a Dravet syndrome phenotype which is more severe than average. This first report of a de novo homozygous variant in the SCN1A gene, therefore, provides a clear illustration of a complex genotype-phenotype relationship.

Molecular Pathways within Autism Spectrum Disorder Endophenotypes.

Autism spectrum disorder (ASD) is a condition that includes a number of neurodevelopmental mental disorders. Recent genetic/genomic investigations have reported an increased prevalence of copy number variations (CNVs) in individuals with autism. Despite the extensive evidence of a genetic component, the genes involved are not known and the background is heterogeneous among subjects. As such, it is highly likely that multiple events (molecular cascades) are implicated in the development of autism. The aim of this work was to shed some light on the biological background behind this condition. We hypothesized that the heterogeneous alterations found within different individuals may converge into one or more specific biological functions (pathways) linked to the heterogeneous phenotypes commonly observed in subjects with ASD. We analyzed a sample of 107 individuals for CNV alterations and checked the genes located within the altered loci (1366). Then, we characterized the subjects for distinct phenotypes. After creating subsamples based on symptoms, the CNVs related to each specific symptom were used to create distinct networks associated with each phenotype (18 in total in the sample under analysis). These networks were independently clustered and enriched to identify potential common pathways involved in autism and variably combined with the clinical phenotype. The first 10 pathways of the analysis are discussed.

Smith-Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort.

Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization.

Neuroligin 4 X-linked (NLGN4X) is an X-linked postsynaptic scaffolding protein, with functional role in excitatory synapsis development and maintenance, that has been associated with neuropsychiatric disorders such as intellectual disability, autism spectrum disorders (ASD), anxiety, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. Chromosomal microarray analysis identified a paternally inherited, 445 Kb deletion on Xp22.3 that includes the entire NLGN4X in a 2.5 year old female (46,XX) with congenital hypotonia, strabismus, ASD, and increased aggressive behavioral issues. Her family history is significant for a mother with learning disabilities, a father with anxiety, major depressive disorder, and substance abuse, as well as two maternal half-brothers with developmental delays. X-inactivation studies in the proband's blood showed random X-inactivation despite the presence of an abnormal X chromosome. Furthermore, trio exome sequencing did not reveal any other deleterious variant that could explain her phenotype. Our report describes the first example of a paternally inherited NLGN4X microdeletion as the genetic etiology of ASD in a female proband, and the psychiatric phenotypes in the father. It also provides further evidence that NLGN4X is sensitive to dosage changes in females, and can contribute to a variety of psychiatric features within the same family.

Early childhood psychosocial family risks and cumulative dopaminergic sensitizing score: Links to behavior problems in U.S. 9-year-olds.

BACKGROUND: We examined, (a) whether in early childhood exposure to risky family environment in different domains (socioeconomic, mental, parenting practices, health behavior, and child-related risks) and accumulatively across various domains (cumulative risk) is associated with child's problem behavior at age 9, and (b) whether the association is more pronounced in children carrying cumulative dopaminergic sensitizing genotype or living in low-income families. METHODS: Participants were 2,860 9-year old children (48% females; 48% Black) and their mothers from the 'Fragile Families and Child Wellbeing Study', a probability birth cohort from large U.S. cities. Mothers responded to questions on child's problem behavior (CBCL). Children responded to questions about their vandalism and substance use. RESULTS: Cumulative family risk was associated with higher internalizing and externalizing behavior and higher vandalism and substance use. All domain-specific risk clusters were associated with higher internalizing behavior and, with the exception of child-related risk, with higher externalizing behavior. Mental health risks, risky parenting practices, and risky health behavior were associated with higher vandalism. Risky parenting practices were associated with higher substance use. The associations were robust to adjustment for cumulative dopaminergic sensitizing genotype. No G x E interactions with dopaminergic genotype and family SES were observed. LIMITATIONS: Sample size was relatively small for genetic analysis and polygenic risk scores were not available. CONCLUSIONS: Exposure to cumulative psychosocial family risks from early childhood is associated with early indicators of problem behavior in adolescence.

Gene co-expression networks in peripheral blood capture dimensional measures of emotional and behavioral problems from the Child Behavior Checklist (CBCL).

The U.S. National Institute of Mental Health (NIMH) introduced the research domain criteria (RDoC) initiative to promote the integration of information across multiple units of analysis (i.e., brain circuits, physiology, behavior, self-reports) to better understand the basic dimensions of behavior and cognitive functioning underlying normal and abnormal mental conditions. Along those lines, this study examined the association between peripheral blood gene expression levels and emotional and behavioral problems in school-age children. Children were chosen from two age- and sex-matched groups: those with or without parental reports of any prior or current psychiatric diagnosis. RNA-sequencing was performed on whole blood from 96 probands aged 6-12 years who were medication-free at the time of assessment. Module eigengenes were derived using weighted gene co-expression network analysis (WGCNA). Associations were tested between module eigengene expression levels and eight syndrome scales from parent ratings on the Child Behavior Checklist (CBCL). Nine out of the 36 modules were significantly associated with at least one syndrome scale measured by the CBCL (i.e., aggression, social problems, attention problems, and/or thought problems) after accounting for covariates and correcting for multiple testing. Our study demonstrates that variation in peripheral blood gene expression relates to emotional and behavioral profiles in children. If replicated and validated, our results may help in identifying problem or at-risk behavior in pediatric populations, and in elucidating the biological pathways that modulate complex human behavior.

The level of GNE and its relationship with behavioral phenotypes in children with autism spectrum disorder.

Autism spectrum disorder (ASD) is a serious nervous system disease, and the cause is not known. Sialic acid (SA) is an indispensable nutrient for early brain development. In previous study, it was found that the SA level of ASD group was lower than that of control group. However, the reason for this has not well explained. A case-control study was conducted to understand the association between the SA synthase enzyme regulatory gene and ASD. The study sample included 65 ASD children and 64 healthy children. The levels of the GNE gene were measured, which encodes UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE), a key enzyme in SA biosynthesis. The symptom severity, intelligence development level, and behavioral performance of ASD children were estimated. There was a significant difference in the levels of GNE between the ASD and control groups (t = 2.028, P = .045). Moreover, the levels of GNE were negatively related to stereotypical behaviors according to the Autism Diagnostic Observation Schedule (ADOS) assessment (r = -0.386, P = .039). However, there is no the correlation between the levels of GNE and autistic severity. As evaluated through the Social Responsiveness Scale (SRS), the levels of GNE were negatively associated with autistic mannerisms scores, social cognition scores and SRS total scores in the children with ASD (r = -0.314, P = .020). These results indicate that the GNE gene may be associated with autism spectrum disorder, and it is also related to autistic behavioral performance, such as stereotypical behaviors, autistic mannerisms, and social cognition ability. Our data suggest that future studies to explore the causal relationship between GNE and the etiology of ASD may be needed.

Comparing the genetic architecture of childhood behavioral problems across socioeconomic strata in the Netherlands and the United Kingdom.

Socioeconomic status (SES) affects the development of childhood behavioral problems. It has been frequently observed that children from low SES background tend to show more behavioral problems. There also is some evidence that SES has a moderating effect on the causes of individual differences in childhood behavioral problems, with lower heritability estimates and a stronger contribution of environmental factors in low SES groups. The aim of the present study was to examine whether the genetic architecture of childhood behavioral problems suggests the presence of protective and/or harmful effects across socioeconomic strata, in two countries with different levels of socioeconomic disparity: the Netherlands and the United Kingdom. We analyzed data from 7-year-old twins from the Netherlands Twin Register (N = 24,112 twins) and the Twins Early Development Study (N = 19,644 twins). The results revealed a nonlinear moderation effect of SES on the contribution of genetic and environmental factors to individual differences in childhood behavioral problems. The heritability was higher, the contribution of the shared environment was lower, and the contribution of the nonshared environment was higher, for children from high SES families, compared to children from low or medium SES families. The pattern was similar for Dutch and UK families. We discuss the importance of these findings for prevention and intervention goals.

The Association Between Genetic Predisposition and Parental Socialization: An Examination of Gene-Environment Correlations Using an Adoption-Based Design.

An extensive body of research has examined the role that genetic influences play in the development of antisocial behavior. Even so, there remains much that is unknown regarding the intersections among antisocial behavior, environments, and genetic influences. The current study is designed to shed some light on this issue by examining whether gene-environment correlations are present in the lives of adopted adolescents. More specifically, this article seeks to contribute to scholarship efforts aimed at understanding whether biological parents' antisocial behavioral phenotypes-behaviors often attributed to an increased likelihood of receiving a genetic propensity for antisocial behaviors-predict variation in environments that are experienced by their adopted-away offspring. To do so, the biological parents of adoptees were assessed and used to identify ways in which children elicit certain responses from their adoptive parents based, in part, on their genotype. Correlational analyses were calculated on a sample of adoptees (the final analytic sample ranged between n = 229 and n = 293) drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health). The results of the study revealed very little evidence of gene-environment correlations. The implications of these findings are considered.

Parenting, Effortful Control, and Adolescents' Externalizing Problem Behavior: Moderation by Dopaminergic Genes.

Research shows that genetics and effortful control play an important role in the link between parenting and problem behavior. However, little is known about how these factors act simultaneously. This article used a moderated mediation model to examine whether effortful control mediated the link between parenting and externalizing problem behavior, and whether dopaminergic genes (i.e., polygenic index score including DAT1, DRD2, DRD4, COMT) moderated this link. Two three-wave studies were conducted on community samples (adolescents: Study 1: N = 457; Mage = 15.74; Study 2: N = 221; Mage = 12.84). There was no mediation by effortful control, but a moderation by dopaminergic reactivity was observed. Despite inconsistent evidence, this article indicates that the development of externalizing problem behavior is subject to genetic characteristics and parenting.

Twins Early Development Study: A Genetically Sensitive Investigation into Behavioral and Cognitive Development from Infancy to Emerging Adulthood.

The Twins Early Development Study (TEDS) is a longitudinal twin study that recruited over 16,000 twin-pairs born between 1994 and 1996 in England and Wales through national birth records. More than 10,000 of these families are still engaged in the study. TEDS was and still is a representative sample of the population in England and Wales. Rich cognitive and emotional/behavioral data have been collected from the twins from infancy to emerging adulthood, with data collection at first contact and at ages 2, 3, 4, 7, 8, 9, 10, 12, 14, 16, 18 and 21, enabling longitudinal genetically sensitive analyses. Data have been collected from the twins themselves, from their parents and teachers, and from the UK National Pupil Database. Genotyped DNA data are available for 10,346 individuals (who are unrelated except for 3320 dizygotic co-twins). TEDS data have contributed to over 400 scientific papers involving more than 140 researchers in 50 research institutions. TEDS offers an outstanding resource for investigating cognitive and behavioral development across childhood and early adulthood and actively fosters scientific collaborations.

Children of the Twins Early Development Study (CoTEDS): A Children-of-Twins Study.

The Children of the Twins Early Development Study (CoTEDS) is a new prospective children-of-twins study in the UK, designed to investigate intergenerational associations across child developmental stages. CoTEDS will enable research on genetic and environmental factors that underpin parent-child associations, with a focus on mental health and cognitive-related traits. Through CoTEDS, we will have a new lens to examine the roles that parents play in influencing child development, as well as the genetic and environmental factors that shape parenting behavior and experiences. Recruitment is ongoing from the sample of approximately 20,000 contactable adult twins who have been enrolled in the Twins Early Development Study (TEDS) since infancy. TEDS twins are invited to register all offspring to CoTEDS at birth, with 554 children registered as of May 2019. By recruiting the second generation of TEDS participants, CoTEDS will include information on adult twins and their offspring from infancy. Parent questionnaire-based data collection is now underway for 1- and 2-year-old CoTEDS infants, with further waves of data collection planned. Current data collection includes the following primary constructs: child mental health, temperament, language and cognitive development; parent mental health and social relationships; parenting behaviors and feelings; and other socioecological factors. Measurement tools have been selected with reference to existing genetically informative cohort studies to ensure overlap in phenotypes measured at corresponding stages of development. This built-in study overlap is intended to enable replication and triangulation of future analyses across samples and research designs. Here, we summarize study protocols and measurement procedures and describe future plans.

Interaction effect of oxytocin receptor (OXTR) rs53576 genotype and maternal postpartum depression on child behavioural problems.

Previous studies have reported interaction effects of oxytocin receptor genotype (rs53576) and environmental factors on mental health in youth. However, the findings are mixed, especially regarding the type of allele (i.e., A vs. G), and it remains unanswered whether such an interaction presents at an early stage of development. Thus, using a unique longitudinal birth cohort sample in Japan (n = 568), we examined whether there was an effect of the interaction between the OXTR rs53576 genotype and maternal postpartum depression, as an environmental risk, on behavioural problems in children. Child behavioural problems (internalising and externalising problems) were ascertained using the Strengths and Difficulties Questionnaire when children were 6 years old. Maternal postpartum depression was measured using the Edinburgh Postnatal Depression Scale when children were at 2 months and 10 months of age. The results revealed a significant effect in the interaction between OXTR rs53576 genotype and maternal postpartum depression on externalising problems in children with AA genotype (ß = 0.136, 95% CI 0.032 to 0.240), but not in those with GG/GA genotype. This indicates that an interaction of vulnerable genotypes (i.e., A allele of OXTR rs53576) with an environmental burden (i.e. maternal postpartum depression) may be one of the potential elements that predisposes the infant to developing behavioural problems early in life. Hence, special attention needs to be paid to children exposed to environmental risks such as maternal postpartum depression, to facilitate the provision of appropriate care.

Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder.

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10-6). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.

Genetic Correlation between Child Callous-Unemotional Behaviors and Fear Recognition Deficit: Evidence for a Neurocognitive Endophenotype.

This study investigates emotion recognition deficits as candidate neurocognitive endophenotypes for callous-unemotional (CU) behaviors. Using a twin design, we tested genetic correlations between child CU behaviors and poor processing of fearful and sad facial expressions. Participants were 504 twin pairs (209 MZ pairs; 295 DZ pairs) from the Quebec Newborn Twin Study, a longitudinal study of a population-based sample of twins. Teachers in kindergarten and first grade rated children's CU behaviors and other behavior problems (attention deficit and hyperactivity symptoms, physical aggression, and depressive symptoms). In first grade (mean age 7 years), the children completed the visual subtest of the Diagnostic Analysis of Nonverbal Accuracy Scale 2 (DANVA-II) to assess emotion recognition from facial stimuli. Using structural equation modeling, we examined the genetic-environmental etiology of the association between fear/sadness recognition and child CU behaviors, controlling for other behavior problems and recognition of other emotions. We found a significant genetic correlation between poor fear recognition and CU behaviors that was independent of other behavior problems. Poor recognition of sadness was not significantly associated with CU behaviors after taking into account other behavior problems. Our results suggest that CU behaviors and fear recognition have a partly shared genetic aetiology. This provides support for poor fear recognition as a key neurocognitive endophenotype for CU behaviors. Future research should test a hypothesized causal chain from specific genes, through amygdala functioning and fear recognition, to CU behaviors, and identify specific environmental factors (including intervention) that may disrupt this chain.

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function.

Addictions are highly heritable disorders, with heritability estimates ranging from 39% to 72%. Multiple studies suggest a link between paternal drug abuse and addiction in their children. However, patterns of inheritance cannot be explained purely by Mendelian genetic mechanisms. Exposure to drugs of abuse results in epigenetic changes that may be passed on through the germline. This mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring. Recent studies have begun to investigate the effect of paternal drug exposure on behavioral and neurobiological phenotypes in offspring of drug-exposed fathers in rodent models. This review aims to discuss behavioral and neural effects of paternal exposure to alcohol, cocaine, opioids, and nicotine. Although a special focus will be on addiction-relevant behaviors, additional behavioral effects including cognition, anxiety, and depressive-like behaviors will be discussed.

Interplay between genome-wide implicated genetic variants and environmental factors related to childhood antisocial behavior in the UK ALSPAC cohort.

We investigated gene-environment (G × E) interactions related to childhood antisocial behavior between polymorphisms implicated by recent genome-wide association studies (GWASs) and two key environmental adversities (maltreatment and smoking during pregnancy) in a large population cohort (ALSPAC). We also studied the MAOA candidate gene and addressed comorbid attention-deficit/hyperactivity disorder (ADHD). ALSPAC is a large, prospective, ethnically homogeneous British cohort. Our outcome consisted of mother-rated conduct disorder symptom scores at age 7;9 years. G × E interactions were tested in a sex-stratified way (α = 0.0031) for four GWAS-implicated variants (for males, rs4714329 and rs9471290; for females, rs2764450 and rs11215217), and a length polymorphism near the MAOA-promoter region. We found that males with rs4714329-GG (P = 0.0015) and rs9471290-AA (P = 0.0001) genotypes were significantly more susceptible to effects of smoking during pregnancy in relation to childhood antisocial behavior. Females with the rs11215217-TC genotype (P = 0.0018) were significantly less susceptible to effects of maltreatment, whereas females with the MAOA-HL genotype (P = 0.0002) were more susceptible to maltreatment effects related to antisocial behavior. After adjustment for comorbid ADHD symptomatology, aforementioned G × E's remained significant, except for rs11215217 × maltreatment, which retained only nominal significance. Genetic variants implicated by recent GWASs of antisocial behavior moderated associations of smoking during pregnancy and maltreatment with childhood antisocial behavior in the general population. While we also found a G × E interaction between the candidate gene MAOA and maltreatment, we were mostly unable to replicate the previous results regarding MAOA-G × E's. Future studies should, in addition to genome-wide implicated variants, consider polygenic and/or multimarker analyses and take into account potential sex stratification.

Genetic moderation of the effects of the Family Check-Up intervention on children's internalizing symptoms: A longitudinal study with a racially/ethnically diverse sample.

Development involves synergistic interplay among genotypes and the physical and cultural environments, and integrating genetics into experimental designs that manipulate the environment can improve understanding of developmental psychopathology and intervention efficacy. Consistent with differential susceptibility theory, individuals can vary in their sensitivity to environmental conditions including intervention for reasons including their genotype. As a consequence, understanding genetic influences on intervention response is critical. Empirically, we tested an interaction between a genetic index representing sensitivity to the environment and the Family Check-Up intervention. Participants were drawn from the Early Steps Multisite randomized prevention trial that included a low-income and racially/ethnically diverse sample of children and their families followed longitudinally (n = 515). As hypothesized, polygenic sensitivity to the environment moderated the effects of the intervention on 10-year-old children's symptoms of internalizing psychopathology, such that children who were genetically sensitive and were randomly assigned to the intervention had fewer symptoms of child psychopathology than genetically sensitive children assigned to the control condition. A significant difference in internalizing symptoms assessed with a clinical interview emerged between the intervention and control groups for those 0.493 SD above the mean on polygenic sensitivity, or 25% of the sample. Similar to personalized medicine, it is time to understand individual and sociocultural differences in treatment response and individualize psychosocial interventions to reduce the burden of child psychopathology and maximize well-being for children growing up in a wide range of physical environments and cultures.