Catharina E. M. van Beijsterveldt

The Young Netherlands Twin Register (YNTR): Longitudinal Twin and Family Studies in Over 70,000 Children

The Netherlands Twin Register (NTR) began in 1987 with data collection in twins and their families, including families with newborn twins and triplets. Twenty-five years later, the NTR has collected at least one survey for 70,784 children, born after 1985. For the majority of twins, longitudinal data collection has been done by age-specific surveys. Shortly after giving birth, mothers receive a first survey with items on pregnancy and birth. At age 2, a survey on growth and achievement of milestones is sent. At ages 3, 7, 9/10, and 12 parents and teachers receive a series of surveys that are targeted at the development of emotional and behavior problems. From age 14 years onward, adolescent twins and their siblings report on their behavior problems, health, and lifestyle. When the twins are 18 years and older, parents are also invited to take part in survey studies. In sub-groups of different ages, in-depth phenotyping was done for IQ, electroencephalography , MRI, growth, hormones, neuropsychological assessments, and cardiovascular measures. DNA and biological samples have also been collected and large numbers of twin pairs and parents have been genotyped for zygosity by either micro-satellites or sets of short nucleotide polymorphisms and repeat polymorphisms in candidate genes. Subject recruitment and data collection is still ongoing and the longitudinal database is growing. Data collection by record linkage in the Netherlands is beginning and we expect these combined longitudinal data to provide increased insights into the genetic etiology of development of mental and physical health in children and adolescents.

Genetic and Environmental Stability in Attention Problems Across the Lifespan: Evidence From the Netherlands Twin Register

OBJECTIVE To review findings on attention-deficit/hyperactivity disorder and attention problems (AP) in children, adolescents, and adults, as established in the database of the Netherlands Twin Register and increase the understanding of stability in AP across the lifespan as a function of genetic and environmental influences. METHOD A longitudinal model was fitted on Netherlands Twin Register AP scores from 44,607 child (<12-year-old), adolescent (12- to 18-year-old), and adult (>18-year-old) twins. RESULTS Mean AP showed a downward trend with age. Age-to-age correlations ranged from 0.33 (50-≥60 years old) to 0.73 (10-12 years old). Stability in individual differences in AP was due to genetic and environmental factors, and change was due primarily to environmental factors. Nonadditive genetic influences were present from childhood to adulthood. Total genetic variance decreased slightly throughout aging, whereas environmental variance increased substantially with the switch from maternal to self-ratings at 12 years of age. As a result, heritability coefficients decreased from 0.70 to 0.74 in childhood (maternal ratings) to 0.51 to 0.56 in adolescence (self-ratings), and 0.40 to 0.54 in adulthood (self-ratings). In childhood, male subjects scored higher than female subjects. After the rater switch at 12 years of age, female subjects tended to score higher than male subjects. CONCLUSIONS Stability of AP is the result of genetic and environmental stability. The decrease in estimated heritability at 12 years of age is due to an increase in occasion-specific environmental variance and likely reflects a methodologic effect. Because environmental influences have lasting effects on AP, their early detection is crucial.

Evidence for a causal association of low birth weight and attention problems

OBJECTIVE Low birth weight (LBW) is associated with attention problems (AP) and attention-deficit/hyperactivity disorder (ADHD). The etiology of this association is unclear. We investigate whether there is a causal influence of birth weight (BW) on AP and whether the BW effect is mediated by catch-up growth (CUG) in low-BW children. METHOD Longitudinal data from >29,000 twins registered with the Netherlands Twin Register with BW ≥1,500 g and gestational age (GA) ≥32 weeks were analyzed with the cotwin control method. Hyperactivity and AP were assessed at ages 3, 7, 10, and 12 years; weight was assessed at birth and age 2 years. RESULTS Children in the lowest BW category of 1,500 to 2,000 g scored 0.18 to 0.37 standard deviations (SD) higher on AP than children in the reference category of 3,000 to 3,500 g. This effect was present in term-born and preterm-born children. Importantly, in BW discordant monozygotic (MZ), dizygotic (DZ), and unrelated (UR) pairs, the child with the lower BW scored higher on hyperactivity and AP than the child with the higher BW and within-pair differences were similar for MZ, DZ, and UR pairs. This pattern is consistent with a causal effect of BW on AP. MZ and DZ twin pairs concordant for LBW but discordant for CUG showed similar AP scores, thus ruling out any effect of CUG on AP. CONCLUSIONS These results strongly indicate that the association of birth weight and AP represents a causal relationship. The effects of BW are not explained by CUG in LBW children.

Heritability Estimates of Body Size in Fetal Life and Early Childhood

Background The objective was to estimate the heritability for height and weight during fetal life and early childhood in two independent studies, one including parent and singleton offsprings and one of mono- and dizygotic twins. Methods This study was embedded in the Generation R Study (n = 3407, singletons) and the Netherlands Twin Register (n = 33694, twins). For the heritability estimates in Generation R, regression models as proposed by Galton were used. In the Twin Register we used genetic structural equation modelling. Parental height and weight were measured and fetal growth characteristics (femur length and estimated fetal weight) were measured by ultrasounds in 2nd and 3rd trimester (Generation R only). Height and weight were assessed at multiple time-points from birth to 36 months in both studies. Results Heritability estimates for length increased from 2nd to 3rd trimester from 13% to 28%. At birth, heritability estimates for length in singletons and twins were both 26% and 27%, respectively, and at 36 months, the estimates for height were 63% and 72%, respectively. Heritability estimates for fetal weight increased from 2nd to 3rd trimester from 17% to 27%. For birth weight, heritability estimates were 26% in singletons and 29% in twins. At 36 months, the estimate for twins was 71% and higher than for singletons (42%). Conclusions Heritability estimates for height and weight increase from second trimester to infancy. This increase in heritability is observed in singletons and twins. Longer follow-up studies are needed to examine how the heritability develops in later childhood and puberty.

A genome-wide association meta-analysis of preschool internalizing problems

OBJECTIVE Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL). METHOD First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT. RESULTS Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p < .03). CONCLUSION Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders.

A prospective study of the effects of breastfeeding and FADS2 polymorphisms on cognition and hyperactivity/attention problems

Breastfeeding has been associated with improved cognitive functioning. There is a beneficial effect on IQ, and possibly on associated phenotypes such as attention problems. It has been suggested that the effect on IQ is moderated by polymorphisms in the FADS2 gene, which is involved in fatty acid metabolism. In this study we tested the relation between breastfeeding and FADS2 polymorphisms on the one hand and IQ, educational attainment, overactivity, and attention problems on the other hand. IQ at age 5, 7, 10, 12, and/or 18 (n = 1,313), educational attainment at age 12 (n = 1,857), overactive behavior at age 3 (n = 2,560), and attention problems assessed at age 7, 10, and 12 years (n = 2,479, n = 2,423, n = 2,226) were predicted by breastfeeding and two SNPs in FADS2 (rs174575 and rs1535). Analyses were performed using structural equation modeling. After correction for maternal education, a main effect of breastfeeding was found for educational attainment at age 12 and overactive behavior at age 3. For IQ, the effect of breastfeeding across age was marginally significant (P = 0.05) and amounted to 1.6 points after correcting for maternal education. Neither a main effect of the FADS2 polymorphisms nor an interaction with breastfeeding was detected for any of the phenotypes. This developmentally informed study confirms that breastfeeding is associated with higher educational attainment at age 12, less overactive behavior at age 3 and a trend toward higher IQ after correction for maternal education. In general, the benefits of breastfeeding were small and did not interact with SNPs in FADS2.

Longitudinal Heritability of Childhood Aggression

The genetic and environmental contributions to the variation and longitudinal stability in childhood aggressive behavior were assessed in two large twin cohorts, the Netherlands Twin Register (NTR), and the Twins Early Development Study (TEDS; United Kingdom). In NTR, maternal ratings on aggression from the Child Behavior Checklist (CBCL) were available for 10,765 twin pairs at age 7, for 8,557 twin pairs at age 9/10, and for 7,176 twin pairs at age 12. In TEDS, parental ratings of conduct disorder from the Strength and Difficulty Questionnaire (SDQ) were available for 6,897 twin pairs at age 7, for 3,028 twin pairs at age 9 and for 5,716 twin pairs at age 12. In both studies, stability and heritability of aggressive behavioral problems was high. Heritability was on average somewhat, but significantly, lower in TEDS (around 60%) than in NTR (between 50% and 80%) and sex differences were slightly larger in the NTR sample. In both studies, the influence of shared environment was similar: in boys shared environment explained around 20% of the variation in aggression across all ages while in girls its influence was absent around age 7 and only came into play at later ages. Longitudinal genetic correlations were the main reason for stability of aggressive behavior. Individual differences in CBCL‐Aggressive Behavior and SDQ‐Conduct disorder throughout childhood are driven by a comparable but significantly different genetic architecture.

A comparison of perinatal outcomes in singletons and multiples born after in vitro fertilization or intracytoplasmic sperm injection stratified for neonatal risk criteria.

To compare perinatal singleton and multiple outcomes in a large Dutch in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) population and within risk subgroups. Newborns were assigned to a risk category based on gestational age, birthweight, Apgar score and congenital malformation.

Twins, Tissue, and Time: An Assessment of SNPs and CNVs

With the desire to assess genetic variation across the lifespan in large-scale collaborative projects, one question is whether inference of copy number (CN) is sensitive to the source of material for deoxyribonucleic acid (DNA) analysis (e.g., blood and buccal) and another question is whether CN is stable as individual sage. Here, we address these questions by applying Affymetrix 6.0 single nucleotide polymorphism (SNP)micro-arrays to 1,472 DNA samples from 710 individuals from the Netherlands Twin Register, including twin and non-twin individuals (372 with buccal and blood derived DNA and 388 with longitudinal data).Similar concordance for CN and genotype inference between samples from the same individual [or from the monozygotic (MZ) co-twins] was found for blood and buccal tissues. There was a small but statistically significant decrease in across-tissue concordance compared with concordance of samples from the same tissue type. No temporal effect was seen on CN variation from the 388 individuals sampled at two time points ranging from 1 to 12 years apart. The majority of our individuals were sampled at age younger than 20 years. Genotype concordance was very high (~ > 99%) between co-twins from 43 MZ pairs. For75 dizygotic (DZ) pairs, ~was ~65%. CN estimates were highly consistent between co-twins from MZ pairs for both deletions (f?2 ~ 90%) and duplications (~ ~ 86%). For DZ, these were similar for within-individual comparisons, but naturally lower between co-twins (~ ~ 50-60%). These results suggest that DNA from buccal samples perform as well as DNA from blood samples on the current generation of micro-array technologies.

Genetic Overlap Between Schizophrenia and Developmental Psychopathology: Longitudinal and Multivariate Polygenic Risk Prediction of Common Psychiatric Traits During Development

Background Several nonpsychotic psychiatric disorders in childhood and adolescence can precede the onset of schizophrenia, but the etiology of this relationship remains unclear. We investigated to what extent the association between schizophrenia and psychiatric disorders in childhood is explained by correlated genetic risk factors. Methods Polygenic risk scores (PRS), reflecting an individuals genetic risk for schizophrenia, were constructed for 2588 children from the Netherlands Twin Register (NTR) and 6127 from the Avon Longitudinal Study of Parents And Children (ALSPAC). The associations between schizophrenia PRS and measures of anxiety, depression, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder/conduct disorder (ODD/CD) were estimated at age 7, 10, 12/13, and 15 years in the 2 cohorts. Results were then meta-analyzed, and a meta-regression analysis was performed to test differences in effects sizes over, age and disorders. Results Schizophrenia PRS were associated with childhood and adolescent psychopathology. Meta-regression analysis showed differences in the associations over disorders, with the strongest association with childhood and adolescent depression and a weaker association for ODD/CD at age 7. The associations increased with age and this increase was steepest for ADHD and ODD/CD. Genetic correlations varied between 0.10 and 0.25. Conclusion By optimally using longitudinal data across diagnoses in a multivariate meta-analysis this study sheds light on the development of childhood disorders into severe adult psychiatric disorders. The results are consistent with a common genetic etiology of schizophrenia and developmental psychopathology as well as with a stronger shared genetic etiology between schizophrenia and adolescent onset psychopathology.