Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.

Intergenerational transmission of body mass index and associations with educational attainment.

BACKGROUND: Individual differences in educational attainment (EA) and physical health, as indexed by body mass index (BMI), are correlated within persons and across generations. The present aim was to assess these associations while controlling for parental transmission. METHODS: We analyzed BMI and EA obtained for 8,866 families from the Netherlands. Data were available for 19,132 persons, including 6,901 parents (mean age 54) and 12,234 of their adult offspring (mean age 32). We employed structural equation modeling to simultaneously model the direct and indirect transmission of BMI and EA from parents to offspring, spousal correlations, and the residual within-person BMI-EA association and tested for gender differences in the transmission parameters. RESULTS: We found moderate intergeneration transmission for BMI (standardized beta ~ .20) and EA (~ .22), and substantial spousal correlations for BMI (.23) and EA (.51). Cross-trait parent to offspring transmission was weak. The strength of transmission was largely independent of parent or offspring gender. Negative within person EA-BMI correlations were observed for all family members (fathers, -0.102; mothers, -0.147; sons, -0.154; daughters, -0.173). About 60% of the EA-BMI correlation in offspring persisted after taking into account the intergeneration transmission. CONCLUSIONS: The intergenerational transmission for BMI and EA is mainly predictive within traits. Significant spousal and within person correlations in the parental generation are responsible for the effect of parental EA on offspring BMI. Offspring EA and BMI are further correlated beyond parental influences.

Higher aggression is related to poorer academic performance in compulsory education.

BACKGROUND: To conduct a comprehensive assessment of the association between aggression and academic performance in compulsory education. METHOD: We studied aggression and academic performance in over 27,000 individuals from four European twin cohorts participating in the ACTION consortium (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies). Individual level data on aggression at ages 7-16 were assessed by three instruments (Achenbach System of Empirically Based Assessment, Multidimensional Peer Nomination Inventory, Strengths and Difficulties Questionnaire) including parental, teacher and self-reports. Academic performance was measured with teacher-rated grade point averages (ages 12-14) or standardized test scores (ages 12-16). Random effect meta-analytical correlations with academic performance were estimated for parental ratings (in all four cohorts) and self-ratings (in three cohorts). RESULTS: All between-family analyses indicated significant negative aggression-academic performance associations with correlations ranging from -.06 to -.33. Results were similar across different ages, instruments and raters and either with teacher-rated grade point averages or standardized test scores as measures of academic performance. Meta-analytical r's were -.20 and -.23 for parental and self-ratings, respectively. In within-family analyses of all twin pairs, the negative aggression-academic performance associations were statistically significant in 14 out of 17 analyses (r = -.17 for parental- and r = -.16 for self-ratings). Separate analyses in monozygotic (r = -.07 for parental and self-ratings), same-sex dizygotic (r's = -.16 and -.17 for parental and self-ratings) and opposite-sex dizygotic (r's = -.21 and -.19 for parental and self-ratings) twin pairs suggested partial confounding by genetic effects. CONCLUSIONS: There is a robust negative association between aggression and academic performance in compulsory education. Part of these associations were explained by shared genetic effects, but some evidence of a negative association between aggression and academic performance remained even in within-family analyses of monozygotic twin pairs.

Safe Linkage of Cohort and Population-Based Register Data in a Genomewide Association Study on Health Care Expenditure.

There are research questions whose answers require record linkage of multiple databases that may be characterized by limited options for full data sharing. For this purpose, the Open Data Infrastructure for Social Science and Economic Innovations (ODISSEI) consortium has supported the development of the ODISSEI Secure Supercomputer (OSSC) platform that allows researchers to link cohort data to data from Statistics Netherlands and run large-scale analyses in a high-performance computing (HPC) environment. Here, we report a successful record linkage genomewide association (GWA) study on expenditure for total health, mental health, primary and hospital care, and medication. Record linkage for genotype data from 16,726 participants from the Netherlands Twin Register (NTR) with data from Statistics Netherlands was accomplished in the secure OSSC platform, followed by gene-based tests and estimation of total and single nucleotide polymorphism (SNP)-based heritability. The total heritability of expenditure ranged between 29.4% (SE 0.8) and 37.5% (SE 0.8), but GWA analyses did not identify SNPs or genes that were genomewide significantly associated with health care expenditure. SNP-based heritability was between 0.0% (SE 3.5) and 5.4% (SE 4.0) and was different from zero for mental health care and primary care expenditure. We conclude that successfully linking genotype data to administrative health care expenditure data from Statistics Netherlands is feasible and demonstrates a series of analyses on health care expenditure. The OSSC platform offers secure possibilities for analyzing linked data in large scale and realizing sample sizes required for GWA studies, providing invaluable opportunities to answer many new research questions.

The (Broad-Sense) Genetic Correlations Among Four Measures of Inattention and Hyperactivity in 12 Year Olds.

We estimated the genetic covariance matrix among four inattention (INATT) and four hyperactivity (HYP) measures in the classical twin design. Data on INATT and HYP symptom counts were obtained in mono- and dizygotic twin pairs (N = 1593) with an average age of 12.2 years (sd = .51). We analyzed maternal ratings of INATT and HYP based on the Conners' Parent Rating Scale (CPRS), the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN), and teacher ratings based on the Conners' Teacher rating scale (CTRS) and the ASEBA Teacher Rating Form (TRF). Broad-sense heritabilities, corrected for the main effects of sex and for random teacher rater effects, were large (ranging from .658 to .912). The results reveal pervasive and strong broad-sense genetic effects on INATT and HYP phenotypes with the phenotypic covariance among the phenotypes largely due to correlated genetic effects. Specifically between 79.9 and 99.9% of the phenotypic covariance among the HYP measures, and between 81.0 and 93.5% of the INATT measures are attributable to broad-sense genetic effects. Overall, the present results, pertaining to the broad-sense heritabilities and shared genetic effects, support the current genome-wide association meta-analytic approach to identifying pleiotropic genetic variants.

Intergenerational Transmission of Education and ADHD: Effects of Parental Genotypes.

It remains a challenge to determine whether children resemble their parents due to nature, nurture, or a mixture of both. Here we used a design that exploits the distinction between transmitted and non-transmitted alleles in genetic transmission from parent to offspring. Two separate polygenic scores (PGS) were calculated on the basis of the transmitted and non-transmitted alleles. The effect of the non-transmitted PGS is necessarily mediated by parental phenotypes, insofar as they contribute to the rearing environment of the offspring (genetic nurturing). We calculated transmitted and non-transmitted PGSs associated with adult educational attainment (EA) and PGSs associated with childhood ADHD in a general population sample of trios, i.e. child or adult offspring and their parents (N = 1120-2518). We tested if the EA and ADHD (non-)transmitted PGSs were associated with childhood academic achievement and ADHD in offspring. Based on the earlier findings for shared environment, we hypothesized to find genetic nurturing for academic achievement, but not for ADHD. In adults, both transmitted (R2 = 7.6%) and non-transmitted (R2 = 1.7%) EA PGSs were associated with offspring EA, evidencing genetic nurturing. In children around age 12, academic achievement was associated with the transmitted EA PGSs (R2 = 5.7%), but we found no support for genetic nurturing (R2 ~ 0.1%). The ADHD PGSs were not significantly associated with academic achievement (R2 ~ 0.6%). ADHD symptoms in children were only associated with transmitted EA PGSs and ADHD PGSs (R2 = 1-2%). Based on these results, we conclude that the associations between parent characteristics and offspring outcomes in childhood are mainly to be attributable to the effects of genes that are shared by parents and children.

Genetic and Environmental Influences on Different Forms of Bullying Perpetration, Bullying Victimization, and Their Co-occurrence.

Bullying comes in different forms, yet most previous genetically-sensitive studies have not distinguished between them. Given the serious consequences and the high prevalence of bullying, it is remarkable that the aetiology of bullying and its different forms has been under-researched. We present the first study to investigate the genetic architecture of bullying perpetration, bullying victimization, and their co-occurrence for verbal, physical and relational bullying. Primary-school teachers rated 8215 twin children on bullying perpetration and bullying victimization. For each form of bullying, we investigated, through genetic structural equation modelling, the genetic and environmental influences on being a bully, a victim or both. 34% of the children were involved as bully, victim, or both. The correlation between being a bully and being a victim varied from 0.59 (relational) to 0.85 (physical). Heritability was ~ 70% for perpetration and ~ 65% for victimization, similar in girls and boys, yet both were somewhat lower for the relational form. Shared environmental influences were modest and more pronounced among girls. The correlation between being a bully and being a victim was explained mostly by genetic factors for verbal (~ 71%) and especially physical (~ 77%) and mostly by environmental factors for relational perpetration and victimization (~ 60%). Genes play a large role in explaining which children are at high risk of being a victim, bully, or both. For victimization this suggests an evocative gene-environment correlation: some children are at risk of being exposed to bullying, partly due to genetically influenced traits. So, genetic influences make some children more vulnerable to become a bully, victim or both.

Pre- and Perinatal Characteristics Associated with Apgar Scores in a Review and in a New Study of Dutch Twins.

A literature review was carried out to identify pre and perinatal characteristics associated with variation in Apgar scores in population-based studies. The parameters identified in the literature search were included in the classical twin design study to estimate effects of pre and perinatal factors shared and nonshared by twins and to test for a contribution of genetic factors in 1- and 5-min Apgar scores in a large sample of Dutch monozygotic (MZ) and dizygotic (DZ) twins. The sample included MZ and DZ twins (N = 5181 pairs) recruited by the Netherlands Twin Register shortly after birth, with data on prenatal characteristics and Apgar scores at first and/or fifth minutes. The ordinal regression and structural equation modeling were used to analyze the effects of characteristics identified in the literature review and to estimate genetic and nongenetic variance components. The literature review identified 63 papers. Consistent with the review, we observed statistically significant effects of birth order, zygosity and gestational age (GA) for 1- and 5-min Apgar scores of both twins. Apgar scores are higher in first-born versus second-born twins and DZ first-born versus MZ first-born twins. Birth weight had an effect on the 5-min Apgar of the first born. Fetal presentation and mode of delivery had different effects on Apgar scores of first- and second-born twins. Parental characteristics and chorionicity did not have significant main effects on Apgar scores. The MZ twins' Apgar correlations equaled the DZ Apgar correlations. Our analyses suggest that individual differences in 1- and 5-min Apgar scores are attributable to shared and nonshared pre and perinatal factors, but not to genotypic factors of the newborns. The main predictors of Apgar scores are birth order, zygosity, GA, birth weight, mode of delivery and fetal presentation.

The Netherlands Twin Register: Longitudinal Research Based on Twin and Twin-Family Designs.

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

Genetic and Environmental Influences on Self-Control: Assessing Self-Control with the ASEBA Self-Control Scale.

This study used a theoretically-derived set of items of the Achenbach System of Empirically Based Assessment to develop the Achenbach Self-Control Scale (ASCS) for 7-16 year olds. Using a large dataset of over 20,000 children, who are enrolled in the Netherlands Twin Register, we demonstrated the psychometric properties of the ASCS for parent-, self- and teacher-report by examining internal and criterion validity, and inter-rater and test-retest reliability. We found associations between the ASCS and measures of well-being, educational achievement, and substance use. Next, we applied the classical twin design to estimate the genetic and environmental contributions to self-control. Genetic influences accounted for 64-75% of the variance in self-control based on parent- and teacher-report (age 7-12), and for 47-49% of the variance in self-control based on self-report (age 12-16), with the remaining variance accounted by non-shared environmental influences. In conclusion, we developed a validated and accessible self-control scale, and show that genetic influences explain a majority of the individual differences in self-control across youth aged 7-16 years.

Overlap Between the General Factor of Personality and Trait Emotional Intelligence: A Genetic Correlation Study.

A previous meta-analysis (Van der Linden et al., Psychol Bull 143:36-52, 2017) showed that the General Factor of Personality (GFP) overlaps with ability as well as trait emotional intelligence (EI). The correlation between trait EI and the GFP was so high (ρ = 0.88) in that meta-analysis that these two may be considered virtually identical constructs. The present study builds on these findings by examining whether the strong phenotypic correlation between the GFP and trait EI has a genetic component. In a sample of monozygotic and dizygotic twins, the heritability estimates for the GFP and trait EI were 53 and 45%, respectively. Moreover, there was a strong genetic correlation of r = .90 between the GFP and trait EI. Additional analyses suggested that a substantial proportion of the genetic correlations reflects non-additive genetic effects (e.g., dominance and epistasis). These findings are discussed in light of evolutionary accounts of the GFP.

Why do children read more? The influence of reading ability on voluntary reading practices.

BACKGROUND: This study investigates the causal relationships between reading and print exposure and investigates whether the amount children read outside school determines how well they read, or vice versa. Previous findings from behavioural studies suggest that reading predicts print exposure. Here, we use twin-data and apply the behaviour-genetic approach of direction of causality modelling, suggested by Heath et al. (), to investigate the causal relationships between these two traits. METHOD: Partial data were available for a large sample of twin children (N = 11,559) and 262 siblings, all enrolled in the Netherlands Twin Register. Children were assessed around 7.5 years of age. Mothers completed questionnaires reporting children's time spent on reading activities and reading ability. Additional information on reading ability was available through teacher ratings and performance on national reading tests. For siblings reading test, results were available. RESULTS: The reading ability of the twins was comparable to that of the siblings and national norms, showing that twin findings can be generalized to the population. A measurement model was specified with two latent variables, Reading Ability and Print Exposure, which correlated .41. Heritability analyses showed that Reading Ability was highly heritable, while genetic and environmental influences were equally important for Print Exposure. We exploited the fact that the two constructs differ in genetic architecture and fitted direction of causality models. The results supported a causal relationship running from Reading Ability to Print Exposure. CONCLUSIONS: How much and how well children read are moderately correlated. Individual differences in print exposure are less heritable than individual differences in reading ability. Importantly, the present results suggest that it is the children's reading ability that determines how much they choose to read, rather than vice versa.

Testing Familial Transmission of Smoking With Two Different Research Designs.

Introduction: Classical twin studies show that smoking is heritable. To determine if shared family environment plays a role in addition to genetic factors, and if they interact (G×E), we use a children-of-twins design. In a second sample, we measure genetic influence with polygenic risk scores (PRS) and environmental influence with a question on exposure to smoking during childhood. Methods: Data on smoking initiation were available for 723 children of 712 twins from the Netherlands Twin Register (64.9% female, median birth year 1985). Children were grouped in ascending order of risk, based on smoking status and zygosity of their twin-parent and his/her co-twin: never smoking twin-parent with a never smoking co-twin; never smoking twin-parent with a smoking dizygotic co-twin; never smoking twin-parent with a smoking monozygotic co-twin; and smoking twin-parent with a smoking or never smoking co-twin. For 4072 participants from the Netherlands Twin Register (67.3% female, median birth year 1973), PRS for smoking were computed and smoking initiation, smoking heaviness, and exposure to smoking during childhood were available. Results: Patterns of smoking initiation in the four group children-of-twins design suggested shared familial influences in addition to genetic factors. PRS for ever smoking were associated with smoking initiation in all individuals. PRS for smoking heaviness were associated with smoking heaviness in individuals exposed to smoking during childhood, but not in non-exposed individuals. Conclusions: Shared family environment influences smoking, over and above genetic factors. Genetic risk of smoking heaviness was only important for individuals exposed to smoking during childhood, versus those not exposed (G×E). Implications: This study adds to the very few existing children-of-twins (CoT) studies on smoking and combines a CoT design with a second research design that utilizes polygenic risk scores and data on exposure to smoking during childhood. The results show that shared family environment affects smoking behavior over and above genetic factors. There was also evidence for gene-environment interaction (G×E) such that genetic risk of heavy versus light smoking was only important for individuals who were also exposed to (second-hand) smoking during childhood. Together, these findings give additional incentive to recommending parents not to expose their children to cigarette smoking.

Attention Deficit Hyperactivity Disorder Symptoms and Low Educational Achievement: Evidence Supporting A Causal Hypothesis.

Attention Deficit Hyperactivity Disorder (ADHD) and educational achievement are negatively associated in children. Here we test the hypothesis that there is a direct causal effect of ADHD on educational achievement. The causal effect is tested in a genetically sensitive design to exclude the possibility of confounding by a third factor (e.g. genetic pleiotropy) and by comparing educational achievement and secondary school career in children with ADHD who take or do not take methylphenidate. Data on ADHD symptoms, educational achievement and methylphenidate usage were available in a primary school sample of ~10,000 12-year-old twins from the Netherlands Twin Register. A substantial group also had longitudinal data at ages 7-12 years. ADHD symptoms were cross-sectionally and longitudinally, associated with lower educational achievement at age 12. More ADHD symptoms predicted a lower-level future secondary school career at age 14-16. In both the cross-sectional and longitudinal analyses, testing the direct causal effect of ADHD on educational achievement, while controlling for genetic and environmental factors, revealed an association between ADHD symptoms and educational achievement independent of genetic and environmental pleiotropy. These findings were confirmed in MZ twin intra-pair differences models, twins with more ADHD symptoms scored lower on educational achievement than their co-twins. Furthermore, children with ADHD medication, scored significantly higher on the educational achievement test than children with ADHD who did not use medication. Taken together, the results are consistent with a direct causal effect of ADHD on educational achievement.

The etiology of autistic traits in preschoolers: a population-based twin study.

BACKGROUND: Autism Spectrum Disorders (ASD) are highly heritable, but the exact etiological mechanisms underlying the condition are still unclear. METHODS: Using a multiple rater twin design in a large sample of general population preschool twins, this study aimed to (a) estimate the contribution of genetic and environmental factors to autistic traits, controlling for the possible effects of rater bias, (b) to explore possible sex differences in etiology and (c) to investigate the discordance in autistic traits in monozygotic and same-sex dizygotic twin pairs. The Netherlands Twin Register collected maternal and paternal ratings on autistic traits from a general population of 38,798 three-year-old twins. Autistic traits were assessed with the DSM-oriented Pervasive Developmental Problems scale of the Child Behavior Check List for preschoolers (1½-5 years). RESULTS: Mother and fathers showed high agreement in their assessment of autistic traits (r = .60-.66). Differences between children in autistic traits were largely accounted for by genetic effects (boys: 78% and girls: 83%). Environmental effects that are unique to a child also played a modest role. Environmental effects shared by children growing up in the same family were negligible, once rater bias was controlled for. While the prevalence for clinical ASD is higher in boys than in girls, this study did not find evidence for striking differences in the etiology of autistic traits across the sexes. Even though the heritability was high, 29% of MZ twin pairs were discordant for high autistic traits (clinical range vs. normal development), suggesting that despite high genetic risk, environmental factors might lead to resilience, unaffected status in the context of genetic risk, in some children. CONCLUSIONS: It is important to focus future research on risk factors that might interplay with a genetic disposition for ASD, but also on protective factors that make a difference in the lives of children at genetic risk.

Bullying and Victimization: The Effect of Close Companionship.

Peer bullying and victimization are a widespread phenomenon among school-age children and can have detrimental effects on the development of children. To examine whether having a close companion during childhood increases or decreases risk of victimization and bullying, this study compared twins to singleton children. A large group of twins (n = 9,909) were included who were compared to their related non-twin siblings (n = 1,534) aged 7-12 from the Netherlands Twin Register, thus creating optimal matching between twins and non-twins. Bullying and victimization were each based on a four-item scale filled out by their teachers. Prevalence rates for either bullying or victimization did not differ between twins and singletons. In total, in the past couple of months, 36% of children bullied peers moderately to severely, and 35% suffered moderately to severely from victimization. Boys were more likely to bully and were more prone to becoming a victim than girls. The most notable finding is that female twin pairs placed together in the same classroom did not bully more often, but were victimized less often, thus pointing to a protective effect of having a close companion in the classroom.

Individual Differences in Exercise Behavior: Stability and Change in Genetic and Environmental Determinants From Age 7 to 18.

Exercise behavior during leisure time is a major source of health-promoting physical activity and moderately tracks across childhood and adolescence. This study aims to investigate the absolute and relative contribution of genes and the environment to variance in exercise behavior from age 7 to 18, and to elucidate the stability and change of genetic and shared environmental factors that underlie this behavior. The Netherlands Twin Register collected data on exercise behavior in twins aged approximately 7, 10, 12, 14, 16 and 18 years (N = 27,332 twins; 48 % males; 47 % with longitudinal assessments). Three exercise categories (low, middle, high) were analyzed by means of liability threshold models. First, a univariate model was fitted using the largest available cross-sectional dataset with linear and quadratic effects of age as modifiers on the means and variance components. Second, a simplex model was fitted on the longitudinal dataset. Heritability was low in 7-year-olds (14 % in males and 12 % in females), but gradually increased up to age 18 (79 % in males and 49 % in females), whereas the initially substantial relative influence of the shared environment decreased with age (from 80 to 4 % in males and from 80 to 19 % in females). This decrease was due to a large increase in the genetic variance. The longitudinal model showed the genetic effects in males to be largely stable and to accumulate from childhood to late adolescence, whereas in females, they were marked by both transmission and innovation at all ages. The shared environmental effects tended to be less stable in both males and females. In sum, the clear age-moderation of exercise behavior implies that family-based interventions might be useful to increase this behavior in children, whereas individual-based interventions might be better suited for adolescents. We showed that some determinants of individual differences in exercise behavior are stable across childhood and youth, whereas others come into play at specific ages. In view of the many benefits of regular exercise, identifying these determinants at specific ages should be a public health priority.

Arithmetic, reading and writing performance has a strong genetic component: A study in primary school children.

Even children attending the same primary school and taught by the same teacher differ greatly in their performance. In the Netherlands, performance at the end of primary school determines the enrollment in a particular level of secondary education. Identifying the impact of genes and the environment on individual differences in educational achievement between children is important. The Netherlands Twin Register has collected data on scores of tests used in primary school (ages 6 to 12) to monitor a child's educational progress in four domains, i.e. arithmetic, word reading, reading comprehension and spelling (1058 MZ and 1734 DZ twin pairs), and of a final test (2451 MZ and 4569 DZ twin pairs) in a large Dutch cohort. In general, individual differences in educational achievement were to a large extent due to genes and the influence of the family environment was negligible. Moreover, there is no evidence for gender differences in the underlying etiology.

Childhood ODD and ADHD Behavior: The Effect of Classroom Sharing, Gender, Teacher Gender and Their Interactions.

One criterion for a diagnostic and statistical manual of mental disorders (DSM-IV) diagnosis of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) is that symptoms are present in at least two settings, and often teacher ratings are taken into account. The short Conners' Teacher Rating Scales-Revised (CTRS-R) is a widely used standardized instrument measuring ODD and ADHD behavior in a school setting. In the current study CTRS-R data were available for 7, 9 and 12-year-old twins from the Netherlands Twin Register. Measurement invariance (MI) across student gender and teacher gender was established for three of the four scales (Oppositional Behavior, Hyperactivity and ADHD Index) of the CTRS-R. The fourth scale (ATT) showed an unacceptable model fit even without constraints on the data and revision of this scale is recommended. Gene-environment (GxE) interaction models revealed that heritability was larger for children sharing a classroom. There were some gender differences in the heritability of ODD and ADHD behavior and there was a moderating effect of teacher's gender at some of the ages. Taken together, this indicates that there was evidence for GxE interaction for classroom sharing, gender of the student and gender of the teacher.