In a longitudinal genetic study we explored which factors underlie stability in verbal and nonverbal abilities, and the extent to which the association between these abilities becomes stronger as ...children grow older. Measures of verbal and nonverbal IQ were collected in Dutch twin pairs at age 5, 7, 10, 12 and 18 years. The stability of both verbal and nonverbal abilities was high, with correlations over time varying from .47 for the 13-year time interval up to .80 for shorter time intervals. Structural equation modeling showed increasing heritability with age, from 48% (verbal) and 64% (nonverbal) at age 5 to 84% and 74% at age 18. Genetic influences seemed to be the driving force behind stability. Stability in nonverbal ability was entirely explained by genes. Continuity in verbal abilities was explained by genetic and shared environmental effects. The overlap between verbal and nonverbal abilities was fully accounted for by genes influencing both abilities. The genetic correlation between verbal and nonverbal IQ increased from .62 in early childhood to .73 in young adulthood.
The Child Behavior Checklist (CBCL) has been used to provide a quantitative description of childhood bipolar disorder (BPAD). Many have reported that children in the clinical range on the Attention ...Problems (AP), Aggressive Behavior (AGG), and Anxious-Depressed (A/D) syndromes simultaneously are more likely to meet the criteria for childhood BPAD. The purpose of this study was to determine if Latent Class Analysis (LCA) could identify heritable phenotypes representing the CBCL-Juvenile Bipolar (CBCL-JBD) profile and whether this phenotype demonstrates increased frequency of suicidal endorsement.
The CBCL data were received by survey of mothers of twins in two large twin samples, the Netherlands Twin Registry. The setting for the study was the general community twin sample. Participants included 6246 10-year-old Dutch twins from the Netherlands Twin Registry. The main outcome measure consisted of the LCA on the items comprising the AP, AGG, and A/D subscales and means from the suicidal items #18 and #91 within classes.
A 7 class model fit best for girls and an 8 class fit best for boys. The most common class for boys or girls was one with no symptoms. The CBCL-JBD phenotype was the least common—about 4%–5% of the boys and girls. This class was the only one that had significant elevations on the suicidal items of the CBCL. Gender differences were present across latent classes with girls showing no aggression without the CBCL-JBD phenotype and rarely showing attention problems in isolation. Evidence of high heritability of these latent classes was found with odds ratios.
In a general population sample, LCA identifies a CBCL-JBD phenotype latent class that is associated with high rates of suicidality, is highly heritable, and speaks to the comorbidity between attention problems, aggressive behavior, and anxious/depression in children.
Puberty is characterized by major changes in hormone levels and structural changes in the brain. To what extent these changes are associated and to what extent genes or environmental influences drive ...such an association is not clear. We acquired circulating levels of luteinizing hormone, follicle stimulating hormone (FSH), estradiol and testosterone and magnetic resonance images of the brain from 190 twins at age 9 9.2 (0.11) years; 99 females/91 males. This protocol was repeated at age 12 12.1 (0.26) years in 125 of these children (59 females/66 males). Using voxel-based morphometry, we tested whether circulating hormone levels are associated with grey matter density in boys and girls in a longitudinal, genetically informative design. In girls, changes in FSH level between the age of 9 and 12 positively associated with changes in grey matter density in areas covering the left hippocampus, left (pre)frontal areas, right cerebellum, and left anterior cingulate and precuneus. This association was mainly driven by environmental factors unique to the individual (i.e. the non-shared environment). In 12-year-old girls, a higher level of circulating estradiol levels was associated with lower grey matter density in frontal and parietal areas. This association was driven by environmental factors shared among the members of a twin pair. These findings show a pattern of physical and brain development going hand in hand.
Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to pre-disposition to metabolic disease. Several studies suggest that LBW resulting from restricted ...intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10(-8)), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (random-effects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.
(1) To determine the prevalence of temporomandibular disorder (TMD)-pain complaints in the general Dutch population; (2) to investigate its relationship with age, sex, educational attainment, and ...country of birth; (3) to determine its association with other pain complaints; and (4) to determine whether there are TMD subgroups (ie, with regard to their sociodemographic variables) that are more vulnerable for comorbid pain complaints.
Data from two large-scale population studies were available: 975 randomly selected adults, who were interviewed by an examiner from the Institute for Applied Scientific Research (TNO), and 11,948 adults who were registered in the Netherlands Twin Register and responded to a survey questionnaire. Chi-squared tests and regression analyses were used to determine whether there were any associations between the presence of TMD pain and the various sociodemographic or comorbid variables.
The prevalence of TMD-pain complaints was 7.2% to 8.0%, and around twice as high in women than in men. The results were inconclusive for association with age, and no evidence was found for an association with country of birth or educational attainment. TMD-pain complaints were strongly related to the presence of other pain complaints. Interestingly, the number of reported comorbid complaints was related to all of the studied sociodemographic variables.
In the general Dutch population, women more often report TMD-pain complaints than men, and patients with TMD-pain complaints more often show other pain complaints than persons without TMD pain. In contrast to common beliefs, no clear association with age was found. Furthermore, widespread pain complaints were more common in non-native Dutch and lower-educated females.
No consensus has been reached yet on how best to characterize children with juvenile bipolar disorder (JBD). Several groups have shown that children on the attention problems (AP), aggressive ...behavior (AGG), and anxious-depressed (AD) syndromes of the Child Behavior Checklist (CBCL) are likely to meet criteria for DSM-JBD. We aimed to use a large population-based twin sample to evaluate the prevalence and genetic architecture of the CBCL-JBD (deviant on AP, AGG, and AD) phenotype and compare these data to children who are deviant on just the CBCL-AP syndrome.
Structural equation modeling (SEM) was applied to CBCL data from 5418, 3562, and 1971 Dutch twin pairs at ages 7, 10, and 12 years.
The CBCL-JBD phenotype occurs in ∼1% of children at each age. Among the children who meet criteria for the CBCL-AP phenotype (∼ 5%), between 13 and 20% also meet criteria for CBCL-JBD. The best SEM for CBCL-JBD includes additive genetic, shared and unique environmental factors. The best SEM for CBCL-AP includes dominant and additive genetic and unique environmental factors.
These data suggest that CBCL-JBD is common, and even more common among children who have severe attention problems. CBCL-JBD shows familial aggregation due to both genetic and shared environmental factors.
In studies of child psychopathology, phenotypes of interest are often obtained by parental ratings. When behavioral ratings are obtained in the context of a twin study, this allows for the ...decomposition of the phenotypic variance, into a genetic and a non-genetic part. If a phenotype is assessed by a single rater, heritability is based on the child’s behavior as expressed in the presence of that particular rater, whereas heritability based on assessments by multiple raters allows for the estimation of the heritability of the phenotype based on rater agreement, as well as the heritability of the rater specific view of the behavior. The aim of this twin study was to quantify the rater common and rater specific contributions to the variation in children’s behavioral problems. We estimated the heritability of maternal and paternal ratings of the Child Behavior Checklist (CBCL) 6–18 empirical emotional and behavioral problem scales in a large sample of 12,310 7-year old Dutch twin pairs. Between 30 and 59% of variation in the part of the phenotype parents agree upon was explained by genetic effects. Common environmental effects that make children in the same family similar explained less variance, ranging between 0 and 32%. For unique views of their children’s behavioral problems, heritability ranged between 0 and 20% for maternal and between 0 and 22% for paternal views. Between 7 and 24% of the variance was accounted for by common environmental factors specific to mother and father’s views. The proportion of rater shared and rater specific heritability can be translated into genetic correlations between parental views and inform the design and interpretation of results of molecular genetic studies. Genetic correlations were nearly or above 0.7 for all CBCL based psychopathology scales. Such large genetic correlations suggest two practical guidelines for genome-wide association studies (GWAS): when studies have collected data from either fathers or mothers, the shared genetic aetiology in parental ratings indicates that is possible to analyze paternal and maternal assessments in a single GWAS or meta-analysis. Secondly, if a study has collected information from both parents, a gain in statistical power may be realized in GWAS by the simultaneous analysis of the data.
More boys than girls with attention deficit hyperactivity disorder (ADHD) receive treatment. One explanation for this bias may be that boys score higher on disruptive behavior scales than girls. ...Although this was supported by findings in clinical samples, recent studies in nonreferred samples showed that boys and girls with ADHD are similar with respect to their levels of disruptive behavior as reported by their mother. In this report, we investigate whether the difference in treatment rate is associated with higher teacher problem scores in boys with ADHD than in girls with ADHD. Data were obtained from mothers and teachers in a nonreferred sample of 283 boys and 291 girls with and without ADHD. Children were selected when they scored either low (controls) or high (probands) on attention problems. Mothers completed DSM-IV interviews, Child Behavior Checklists (CBCL) and the Conners Rating Scale (CRS). Teachers filled in the Teacher Report Form (TRF), and the CRS. Boys and girls with ADHD had similar levels of psychiatric illness and school impairment (such as being held back, special class placement and learning problems) by mother report. Mothers reported similar levels of aggression and attention problems in boys and girls with ADHD. In contrast, teachers consistently rated boys with ADHD as having higher scores on reports of attention problems and aggression than girls with ADHD. Gender differences vary across settings: boys and girls with ADHD are rated as behaving differently at school, but not at home. The higher level of teacher reported problem behavior at school may explain the high male-female ratio for ADHD in clinical settings. These findings have implications for the results of genetic studies that rely on referred samples, as these studies may give a distorted view of sex differences in the population.
Children differ in their ability to learn what is taught at school. Evidence from twin studies suggests that genetic effects contribute to such differences. The aim of the present study was to ...systematically review the existing literature, including 61 studies from 11 cohorts, on twin studies of educational achievement in primary school children. The meta-analysis estimated heritability, based on up to 5330 MZ and 7084 DZ twin pairs, at 73% for reading, 49% for reading comprehension, 57% for mathematics, 44% for spelling, 64% for language and 66% for educational achievement. The importance of genetic effects on educational achievement differed between countries. Heritability was consistently high in the Netherlands across educational domains, while this was not always true for the USA and the UK. It can be concluded that genetic variation is an important contributor to the individual differences in educational achievement, with some indication for interaction with country.
Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this ...study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.
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