The Quebec Newborn Twin Study at 21.

This paper is a revised and updated edition of a previous description of the Quebec Newborn Twin Study (QNTS), an ongoing prospective longitudinal follow-up of a birth cohort of twins born between 1995 and 1998 in the greater Montreal area, Québec, Canada. The goal of QNTS is to document individual differences in the cognitive, behavioral, and social-emotional aspects of developmental health across childhood, their early genetic and environmental determinants, as well as their putative role in later social-emotional adjustment, school, health, and occupational outcomes. A total of 662 families of twins were initially assessed when the twins were aged 6 months. These twins and their family were then followed regularly. QNTS now has 16 waves of data collected or planned, including 5 in preschool. Over the last 24 years, a broad range of physiological, cognitive, behavioral, school, and health phenotypes were documented longitudinally through multi-informant and multimethod measurements. QNTS also entails extended and detailed multilevel assessments of proximal (e.g., parenting behaviors, peer relationships) and distal (e.g., family income) features of the child's environment. QNTS children and a subset of their parents have been genotyped, allowing for the computation of a variety of polygenic scores. This detailed longitudinal information makes QNTS uniquely suited for the study of the role of the early years and gene-environment transactions in development.

Gene-environment processes linking peer victimization and physical health problems: a longitudinal twin study.

OBJECTIVE: This study examined whether (a) a genetic disposition for physical health problems increases the risk of peer victimization and (b) peer victimization interacts with genetic vulnerability in explaining physical health problems. METHODS: Participants were 167 monozygotic and 119 dizyogtic twin pairs. Physical symptoms were assessed in early childhood and early adolescence. Peer victimization was assessed in middle childhood. RESULTS: Genetic vulnerability for physical health problems in early childhood was unrelated to later peer victimization, but genetic vulnerability for physical health problems during early adolescence increased the risk of victimization. Victimization did not interact with genetic factors in predicting physical symptoms. Environmental, not genetic, factors had the greatest influence on the development of physical symptoms in victims. CONCLUSION: Genetic vulnerability for physical health problems in early adolescence increases the risk of peer victimization. Whether victims suffer a further increase in physical symptoms depends on the presence of protective environmental factors.

Genetic and environmental influences on eating behaviors in 2.5- and 9-year-old children: a longitudinal twin study.

BACKGROUND: Eating behaviors during childhood are related both to children's diet quality and to their weight status. A better understanding of the determinants of eating behavior during childhood is essential for carrying out effective dietary interventions. METHODS: We assessed the contribution of genetic and environmental factors to variations in selected eating behaviors in early and late childhood. Information on eating behaviors came from questionnaires administered to parents of children participating in the Quebec Newborn Twin Study when the twins were 2.5 and 9 years old (n = 692 children). Dichotomous variables were derived and analyzed using structural equation modeling, as part of a classic twin study design. We performed univariate and bivariate longitudinal analyses to quantify sources of variation and covariation across ages, for several eating behavior traits. RESULTS: We found moderate to strong heritability for traits related to appetite such as eating too much, not eating enough and eating too fast. Univariate analysis estimates varied from 0.71 (95% CI: 0.49, 0.87) to 0.89 (0.75, 0.96) in younger children and from 0.44 (0.18, 0.66) to 0.56 (0.28, 0.78) in older children. Bivariate longitudinal analyses indicated modest to moderate genetic correlations across ages (r(A) varying from 0.34 to 0.58). Common genetic influences explained 17% to 43% of the phenotypic correlation between 2.5 and 9 years for these appetite-related behaviors. In 9-year-old children, food acceptance traits, such as refusing to eat and being fussy about food, had high heritability estimates, 0.84 (0.63, 0.94) and 0.85 (0.59, 0.96) respectively, while in younger children, the shared environment (i.e., common to both twins) contributed most to phenotypic variance. Variances in meal-pattern-related behaviors were mostly explained by shared environmental influences. CONCLUSIONS: Genetic predispositions explain a large part of the variations in traits related to appetite during childhood, though our results suggest that as children get older, appetite-related behaviors become more sensitive to environmental influences outside the home. Still, for several traits environmental influences shared by twins appear to have the largest relative importance. This finding supports the notion that familial context has considerable potential to influence the development of healthy eating habits throughout childhood.

Strong genetic contribution to peer relationship difficulties at school entry: findings from a longitudinal twin study.

This study assessed the genetic and environmental contributions to peer difficulties in the early school years. Twins' peer difficulties were assessed longitudinally in kindergarten (796 twins, Mage = 6.1 years), Grade 1 (948 twins, Mage = 7.1 years), and Grade 4 (868 twins, Mage = 10 years) through multiple informants. The multivariate results revealed that genetic factors accounted for a strong part of both yearly and stable peer difficulties. At the univariate level, the genetic contributions emerged progressively, as did a growing consensus among informants with respect to those who experienced peer difficulties. These results underline the need to intervene early and persistently, and to target the child and the peer context to prevent peer difficulties and their consequences.

The Quebec Newborn Twin Study into adolescence: 15 years later.

The Quebec Newborn Twin Study (QNTS) is an ongoing prospective longitudinal follow-up of a birth cohort of twins born between 1995 and 1998 in the greater Montreal area, Québec, Canada. The goal of QNTS is to document individual differences in the cognitive, behavioral, and social-emotional aspects of developmental health across childhood, their early bio-social determinants, as well as their putative role in later social-emotional adjustment, school and health outcomes. A total of 662 families of twins were initially assessed when the twins were aged 6 months. These twins and their family were then followed regularly. QNTS has 14 waves of data collected or planned, including 5 in preschool. Over the past 15 years, a broad range of physiological, cognitive, behavioral, school, and health phenotypes were documented longitudinally through multi-informant and multi-method measurements. QNTS also entails extended and detailed multi-level assessments of proximal (e.g., parenting behaviors, peer relationships) and distal (e.g., family income) features of the child's environment. This detailed longitudinal information makes QNTS uniquely suited for the study of the role of the early years and gene-environment transactions in development.

Genetic and environmental etiology of disregard for rules.

Disregard for rules, a key component of oppositional defiant and conduct disorders, is stable during early childhood. This study investigates for the first time the relative importance of genetic and environmental factors underlying this early developmental stability. Maternal reports of child disregard for rules were obtained at four time points from 20 to 64 months of age in a population-based twin sample (N = 597 twin pairs, including 238 monozygotic and 359 dizygotic pairs). Structural equation modeling was conducted using both variance-covariance and latent growth curve approaches. Genetic factors accounted for most of the stability in disregard for rules throughout early childhood. In contrast, most environmental effects were age specific. Developmental stability in early symptoms of disregard for rules is best explained by the stable action of genetic factors, suggesting that preventive interventions should take an intergenerational approach, targeting at-risk families as early as possible.

Salivary cortisol levels are associated with resource control in a competitive situation in 19 month-old boys.

Glucocorticoids (GCs) have been related to social rank in many studies across species, a particular rank giving rise to a particular stress-related physiological profile. Our aim was to examine the hypothesis that GCs levels in toddlers would be related to social dominance in a competitive resource situation. Subjects were 376 toddlers from the Quebec Newborn Twin Study. At 19 months of age, each subject was exposed to 2 unfamiliar situations known to be moderately stressful at that age. Saliva was collected before and after the unfamiliar situations, to assess pre-test and reactive cortisol. Then the toddler reaction to a competitive situation for a toy with an unfamiliar peer was assessed and we measured the proportion of time the child controlled the resource. In girls, no association between cortisol levels and the proportion of time the child got the toy was found. On the other hand, in boys, increased cortisol levels before the unfamiliar situation were significantly related to a decreased proportion of time they got the toy in the competitive situation (r(174) = -0.17, P = 0.02). These results show that even in toddlers with limited social experience, association between GCs levels and social dominance can be found, an association that is specific to boys.

Gene-environment processes linking aggression, peer victimization, and the teacher-child relationship.

Aggressive behavior in middle childhood is at least partly explained by genetic factors. Nevertheless, estimations of simple effects ignore possible gene-environment interactions (G × E) or gene-environment correlations (rGE) in the etiology of aggression. The present study aimed to simultaneously test for G × E and rGE processes between aggression, on the one hand, and peer victimization and the teacher-child relationship in school, on the other hand. The sample comprised 124 MZ pairs and 93 DZ pairs assessed in Grade 1 (mean age = 84.7 months). Consistent with rGE, children with a presumed genetic disposition for aggression were at an increased risk of peer victimization, whereas in line with G × E, a positive relationship with the teacher mitigated the genetically mediated expression of aggression.

A monozygotic twin difference study of friends' aggression and children's adjustment problems.

This study used the monozygotic (MZ) twin difference method to examine whether differences in friends' aggression increased the differences in MZ twins' aggression and depressive symptoms from kindergarten to Grade 1 and whether perceived victimization by the friend played a mediating role in this context. Participants were 223 MZ twin pairs. Results showed that differences in kindergarten friends' aggression significantly predicted an increased difference in MZ twins' aggression from kindergarten (mean age = 6.7 years) to Grade 1 (mean age = 7.5 years) for both boys and girls. Differences in perceived victimization by the friend mediated this association, albeit only in boys. Differences in perceived victimization by the friend also predicted an increase in MZ twins' differences in depressive symptoms. These results support the importance of friendship experiences during early childhood.

Neuroanatomy of childhood disruptive behavior disorders.

Our aims were to (1) examine possible neuroanatomical abnormalities associated with the Disruptive Behavior Disorders (DBDs) as a group and (2) assess neuroanatomical anomalies specific to each DBD (i.e., conduct disorder [CD] and oppositional defiant disorder). Cortical thickness analysis and voxel-based morphometry were analyzed in 47 8-year-old boys (22 DBDs with and without CD and/or ODD and 25 healthy controls) from Magnetic Resonance Imaging brain scans. DBD symptoms were assessed using the Dominic-R. In DBD subjects relative to controls, we found (1) a decreased overall mean cortical thickness; (2) thinning of the cingulate, prefrontal and insular cortices; and (3) decreased gray matter density (GMd) in the same brain regions. We also found that scores on the Dominic-R were negatively correlated with GMd in the prefrontal and precuneus/superior temporal regions. There was a subdiagnostic main effect for CD, related to thinning of the middle/medial frontal, and for ODD in the left rectal/orbitofrontal. Findings suggest that thinning and decreased GMd of the insula disorganizes prefrontal circuits, diminishing the inhibitory influence of the prefrontal cortex on anger, aggression, cruelty, and impulsivity, and increasing a person's likelihood of aggressive behavior. These findings have implications for pathophysiologic models of the DBDs, their diagnostic classification system, and for designing more effective intervention programs.

Lateralized genetic and environmental influences on human brain morphology of 8-year-old twins.

It has been increasing rapidly interest in understanding genetic effects on brain structure and function in recent years. In this study, we examined the genetic and environmental influences on the variation in cortical thickness and specific tissue volumes in a large cohort of 8-year-old healthy twins. The present study can provide a better estimation of the genetic and environmental effects by virtue of the homogeneously aged pediatric twin pairs with a similar growing environment. We found that common environmental factors contributed significantly to the variations of the right lateral ventricle (36%) and corpus callosum (36%) volumes while genetic factors accounted for most of the phenotypic variance in other brain tissue volumes. In the case of cortical thickness, several regions in the left hemisphere showed statistically significant additive genetic factors, including the middle and inferior frontal gyri, lateral fronto-orbital and occipitotemporal gyri, pars opercularis, planum temporale, precentral and parahippocampal gyri and the medial region of the primary somatosensory cortex. Relatively high common environmental influence (>50%) was observed in the right anterior cingulate cortex and insula. Our findings indicate that the genetic and common environmental influences on individual human brain structural differences are lateralized, with the language-dominant left cerebral cortex under stronger genetic control than the right.

A Standardized Protocol for Efficient and Reliable Quality Control of Brain Registration in Functional MRI Studies.

Automatic alignment of brain anatomy in a standard space is a key step when processing magnetic resonance imaging for group analyses. Such brain registration is prone to failure, and the results are therefore typically reviewed visually to ensure quality. There is however no standard, validated protocol available to perform this visual quality control (QC). We propose here a standardized QC protocol for brain registration, with minimal training overhead and no required knowledge of brain anatomy. We validated the reliability of three-level QC ratings (OK, Maybe, Fail) across different raters. Nine experts each rated N = 100 validation images, and reached moderate to good agreement (kappa from 0.4 to 0.68, average of 0.54 ± 0.08), with the highest agreement for "Fail" images (Dice from 0.67 to 0.93, average of 0.8 ± 0.06). We then recruited volunteers through the Zooniverse crowdsourcing platform, and extracted a consensus panel rating for both the Zooniverse raters (N = 41) and the expert raters. The agreement between expert and Zooniverse panels was high (kappa = 0.76). Overall, our protocol achieved a good reliability when performing a two level assessment (Fail vs. OK/Maybe) by an individual rater, or aggregating multiple three-level ratings (OK, Maybe, Fail) from a panel of experts (3 minimum) or non-experts (15 minimum). Our brain registration QC protocol will help standardize QC practices across laboratories, improve the consistency of reporting of QC in publications, and will open the way for QC assessment of large datasets which could be used to train automated QC systems.

The effect of template choice on morphometric analysis of pediatric brain data.

The present study investigated the "template effect" on the morphometric analysis of a pediatric brain MRI database obtained from 8-year-old children through various measures of surface and volumetric morphologies. We first constructed an age-appropriate template from an independent set of pediatric brain images and then compared it with a well-known adult brain template, the ICBM152, in terms of the morphometric features that resulted from our pediatric database. The individual cortical surface acquired based on the pediatric template exhibited, on average, a significantly thinner cortex (-1.66+/-1.60%, t=-15.18), larger cortical surface areas (0.31+/-0.70%, t=6.52), and a higher degree of cortical folding (0.08+/-0.13%, t=8.72) while compared with those based on the adult template. We also found a significant increase in the cerebrospinal fluid volume (-2.63+/-4.84) for the adult template based brains and the cortical gray matter (GM) volume (6.10+/-7.81) for the pediatric template based brains. The cross-correlation of pediatric template based individual brain data (0.95 without brain mask) was significantly higher than those of adult template based (0.88) and the amount of deformation during non-linear spatial normalization was significantly reduced when using the pediatric template (average magnitude of deformation in the cortical GM class: 1.71 mm vs. 2.23 mm, t=12.39). In addition, an "internal" pediatric template, taken from the study subjects themselves, was generated and compared with the "external" pediatric template for reference. There was no significant difference between these two pediatric brain templates and associated tissue probability maps. The results show that it is necessary to be cautious when interpreting results from pediatric imaging studies based on adult reference data.

Gene-environment interplay between peer rejection and depressive behavior in children.

BACKGROUND: Genetic risk for depressive behavior may increase the likelihood of exposure to environmental stressors (gene-environment correlation, rGE). By the same token, exposure to environmental stressors may moderate the effect of genes on depressive behavior (gene-environment interaction, GxE). Relating these processes to a peer-related stressor in childhood, the present study examined (1) whether genetic risk for depressive behavior in children is related to higher levels of rejection by the peer group (rGE) and (2) whether peer rejection moderates the effect of genetic factors on children's depressive behavior (GxE). METHODS: The sample comprised 336 twin pairs (MZ pairs = 196, same-sex DZ pairs = 140) assessed in kindergarten (mean age 72.7 months). Peer acceptance/rejection was measured via peer nominations. Depressive behavior was measured through teacher ratings. RESULTS: Consistent with rGE, a moderate overlap of genetic effects was found between peer acceptance/rejection and depressive behavior. In line with GxE, genetic effects on depressive behavior varied across levels of peer acceptance/rejection. CONCLUSIONS: An increased genetic disposition for depressive behavior is related to a higher risk of peer rejection (rGE). However, genes play a lesser role in explaining individual differences in depressive behavior in rejected children than in accepted children (GxE).

Early child language mediates the relation between home environment and school readiness.

Home environment quality is a well-known predictor of school readiness (SR), although the underlying processes are little known. This study tested two hypotheses: (a) child language mediates the association between home characteristics (socioeconomic status and exposure to reading) and SR, and (b) genetic factors partly explain the association between language and SR. Data were collected between 6 and 63 months in a large sample of twins. Results showed that home characteristics had direct effects on SR and indirect effects through child language. No genetic correlation was found between language and SR. These results suggest that home characteristics affect SR in part through their effect on early language skills, and show that this process is mainly environmental rather than genetic in nature.

Validating psychiatric endophenotypes: inhibitory control and attention deficit hyperactivity disorder.

ADHD is a heritable condition of childhood for which several risk alleles have been identified. However, observed effect sizes have been small and few replicated polymorphisms have been identified. There are many reasons for the lack of one-to-one correspondence between genotype and phenotype in ADHD. Endophenotypes are non-clinical markers of genetic risk which may facilitate gene discovery in complex disorders like ADHD. The most common endophenotypes under consideration in ADHD are neuropsychological measures of executive function, although a range of psychological, physiological and neuroanatomical endophenotypes have been proposed. If carefully chosen, endophenotypes have the potential to increase the power of genetic research to identify susceptibility genes. If not carefully selected, endophenotypes may generate false negative and false positive results. This paper reviews the theoretical rationale for endophenotypes and proposes a priori criteria by which ADHD endophenotypes should be selected and validated. The literature on motor response inhibition is reviewed to illustrate the validation process which is recommended in the selection of other candidate endophenotypes.

Gene-environment interaction between peer victimization and child aggression.

Although peer victimization places children at serious risk for aggressive behavior, not all victimized children are aggressive. The diathesis-stress hypothesis of disease proposes that an environmental stressor such as peer victimization should to lead to maladjustment mostly in those individuals with preexisting genetic vulnerabilities. Accordingly, this study examined whether the link between peer victimization and child aggression is moderated by children's genetic risk for such behavior. Using a sample of 506 6-year-old twins, peer victimization was assessed through peer nominations and aggressive behavior was assessed through peer and teacher reports. Children's genetic risk for aggression was estimated as a function of their co-twin's aggression and the pair's zygosity. Genetic modeling showed that peer victimization is an environmentally driven variable that is unrelated to children's genetic disposition. Results also provided support for the notion of a gene-environment interaction between peer victimization and child's genetic risk for aggressive behavior, albeit only in girls. For boys, peer victimization was related to aggression regardless of the child's genetic risk for such behavior. Different socialization experiences in girls' compared to boys' peer groups may explain the different pattern of results for girls and boys.

The development of hyperactive-impulsive behaviors during the preschool years: the predictive validity of parental assessments.

The objectives of this study were to establish the different developmental trajectories of hyperactive-impulsive behaviors on the basis of both mother and father ratings at 19, 32, 50, and 63 months, and to examine the predictive validity of these trajectories with respect to later hyperactive-impulsive behaviors, as rated by teachers in the first 2 years of school. Hyperactive-impulsive behaviors were assessed in a population-based sample of 1,112 twins (565 boys and 547 girls) at 19, 32, 50, and 63 months of age. The results revealed a differentiated and consistent view of developmental trajectories of hyperactive-impulsive behaviors derived from these repeated assessments, with 7.1% of children seen by mothers (7% for fathers) as displaying high and stable hyperactive-impulsive behaviors. According to mother ratings, children on a high-chronic trajectory were more likely than other children to display hyperactive-impulsive behaviors at 72 and 84 months according to their teachers. Repeated measures over time and father-based trajectories significantly added to the prediction teacher later ratings of hyperactive-impulsive behaviors. These results support the predictive validity of parental assessment of hyperactive-impulsive behaviors during the preschool years and their use to identify children at risk for further evaluation and possible intervention.

Association of the dopamine transporter gene and ADHD symptoms in a Canadian population-based sample of same-age twins.

Attention deficit hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder emerging during childhood. Psychostimulant medications (e.g., methylphenidate) noticeably reduce ADHD symptoms in most children. Since methylphenidate inhibits dopamine transporter activity, the dopamine transporter gene (DAT1) was considered to be the prime candidate risk gene in ADHD. Several studies found evidence for an association between the 10-repeat allele of the variable number of tandem repeat (VNTR) located in the 3' untranslated region and ADHD and/or ADHD symptoms in clinical and population-based samples. However, this finding was not replicated in all samples. In this study, we investigated the association between the DAT1 gene and ADHD symptoms in a population-based twin sample from Québec (Canada). We used two polymorphisms, the VNTR and rs27072, the last providing the most significant results in a clinical sample from Toronto (Ontario, Canada). No association was noted between the VNTR and ADHD symptoms in children at 6 and 7 years of age, as reported by teachers. However, a significant association was found for the rs27072 polymorphism and symptoms of inattention and hyperactivity/impulsivity. These findings indicate that the DAT1 gene contributes to ADHD symptoms in this sample and further suggest that the VNTR may not be the optimal polymorphism for study in all populations.

Kindergarten children's genetic vulnerabilities interact with friends' aggression to promote children's own aggression.

OBJECTIVE: To examine whether kindergarten children's genetic liability to physically aggress moderates the contribution of friends' aggression to their aggressive behaviors. METHOD: Teacher and peer reports of aggression were available for 359 6-year-old twin pairs (145 MZ, 212 DZ) as well as teacher and peer reports of aggression of the two best friends of each twin. Children's genetic risk for aggression was based on their cotwin's aggression status and the pair's zygosity. RESULTS: Children's aggression was highly heritable. Unique environment accounted for most of the variance in friends' aggression, although there was also a small genetic contribution (15%). Both genetic liability to aggression and having aggressive friends predicted twins' aggression. However, the contribution of aggressive friends to children's aggression was strongest among genetically vulnerable children. This result was similar for boys and girls, despite sex differences in both aggression and the level of aggression of friends. CONCLUSIONS: Affiliation with aggressive friends at school entry is a significant environmental risk factor for aggression, especially for children genetically at risk for aggressive behaviors. Developmental models of aggression need to take into account both genetic liability and environmental factors in multiple settings, such as the peer context, to more precisely describe and understand the various developmental pathways to aggression. The implications for early prevention programs are discussed.