Suzanne C. Swagerman

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.

Brain SCALE: Brain Structure and Cognition: an Adolescent Longitudinal Twin Study into the Genetic Etiology of Individual Differences

From childhood into adolescence, the childs brain undergoes considerable changes in both structure and function. Twin studies are of great value to explore to what extent genetic and environmental factors explain individual differences in brain development and cognition. In The Netherlands, we initiated a longitudinal study in which twins, their siblings and their parents are assessed at three year intervals. The participants were recruited from The Netherlands Twin Register (NTR) and at baseline consisted of 112 families, with 9-year-old twins and an older sibling. Three years later, 89 families returned for follow-up assessment. Data collection included psychometric IQ tests, a comprehensive neuropsychological testing protocol, and parental and self-ratings of behavioral and emotional problems. Physical maturation was measured through assessment of Tanner stages. Hormonal levels (cortisol, luteinizing hormone, follicle-stimulating hormone, testosterone, and estrogens) were assessed in urine and saliva. Brain scans were acquired using 1.5 Tesla Magnetic Resonance Imaging (MRI), which provided volumetric measures and measures of cortical thickness. Buccal swabs were collected for DNA isolation for future candidate gene and genome-wide analysis studies. This article gives an overview of the study and the main findings. Participants will return for a third assessment when the twins are around 16 years old. Longitudinal twin-sibling studies that map brain development and cognitive function at well-defined ages aid in the understanding of genetic influences on normative brain development.

Development and heritability of subcortical brain volumes at ages 9 and 12

Subcortical brain structures are involved in a variety of cognitive and emotional functions and follow different trajectories of increase and decrease in volume from childhood to adulthood. The heritability of development of subcortical brain volumes during adolescence has not been studied comprehensively. In a longitudinal twin study, we estimated to what extent subcortical brain volumes are influenced by genetic factors at ages 9 and 12. In addition, we assessed whether new genes are expressed at age 12 and whether there is evidence for genotype by sex interaction. Brain scans were acquired for 112 and 89 twin pairs at 9 and 12 years of age. In both boys and girls, there was an increase in volumes of the thalamus, hippocampus, amygdala and pallidum, and a decrease in volumes of the caudate and nucleus accumbens. The putamen showed a decrease in boys bilaterally and an increase in girls in the left hemisphere. Heritability was high (>50%) for all structures – except for the left nucleus accumbens – with heritabilities ranging from 0.50 to 0.91 at age 9, and from 0.59 to 0.88 at age 12. There were no significant new genetic effects coming into play at age 12, and there was no evidence for genotype by sex interactions. These findings suggest that despite their sensitivity to environmental effects, the heritability of subcortical brain structures is high from childhood on, resembling estimates found in adult samples.

Genetic transmission of reading ability.

Graphical abstract Figure. No Caption available. HighlightsWe studied familial transmission of reading ability in twins, siblings and parents.Evidence was found for additive and non‐additive genetic influences.Assortative mating was substantial.Parent‐offspring resemblance was due to genetic transmission not family environment. Abstract Reading is the processing of written language. Family resemblance for reading (dis)ability might be due to transmission of a genetic liability or due to family environment, including cultural transmission from parents to offspring. Familial‐risk studies exploring neurobehavioral precursors for dyslexia and twin studies can only speak to some of these issues, but a combined twin‐family study can resolve the nature of the transmitted risk. Word‐reading fluency scores of 1100 participants from 431 families (with twins, siblings and their parents) were analyzed to estimate genetic and environmental sources of variance, and to test the presence of assortative mating and cultural transmission. Results show that variation in reading ability is mainly caused by additive and non‐additive genetic factors (64%). The substantial assortative mating (rfather–mother = 0.38) has scientific and clinical implications. We conclude that parents and offspring tend to resemble each other for genetic reasons, and not due to cultural transmission.

Genetic associations between intelligence and cortical thickness emerge at the start of puberty

Cognitive abilities are related to (changes in) brain structure during adolescence and adulthood. Previous studies suggest that associations between cortical thickness and intelligence may be different at different ages. As both intelligence and cortical thickness are heritable traits, the question arises whether the association between cortical thickness development and intelligence is due to genes influencing both traits. We study this association in a longitudinal sample of young twins. Intelligence was assessed by standard IQ tests at age 9 in 224 twins, 190 of whom also underwent structural magnetic resonance imaging (MRI). Three years later at age 12, 177/125 twins returned for a follow‐up measurement of intelligence/MRI scanning, respectively. We investigated whether cortical thickness was associated with intelligence and if so, whether this association was driven by genes. At age 9, there were no associations between cortical thickness and intelligence. At age 12, a negative relationship emerged. This association was mainly driven by verbal intelligence, and manifested itself most prominently in the left hemisphere. Cortical thickness and intelligence were explained by the same genes. As a post hoc analysis, we tested whether a specific allele (rs6265; Val66Met in the BDNF gene) contributed to this association. Met carriers showed lower intelligence and a thicker cortex, but only the association between the BDNF genotype and cortical thickness in the left superior parietal gyrus reached significance. In conclusion, it seems that brain areas contributing to (verbal) intellectual performance are specializing under the influence of genes around the onset of puberty. Hum Brain Mapp 35:3760–3773, 2014.

The Computerized Neurocognitive Battery: Validation, aging effects, and heritability across cognitive domains.

OBJECTIVE The Computerized Neurocognitive Battery (CNB) enables efficient neurocognitive assessment. The authors aimed to (a) estimate validity and reliability of the batterys Dutch translation, (b) investigate effects of age across cognitive domains, and (c) estimate heritability of the CNB tests. METHOD A population-representative sample of 1,140 participants (aged 10-86), mainly twin-families, was tested on the CNB, providing measures of speed and accuracy in 14 cognitive domains. In a subsample (246 subjects aged 14-22), IQ data (Wechsler Intelligence Scale for Adults; WAIS) were available. Validity and reliability were assessed by Cronbachs alpha, comparisons of scores between Dutch and U.S. samples, and investigation of how a CNB-based common factor compared to a WAIS-based general factor of intelligence (g). Linear and nonlinear age dependencies covering the life span were modeled through regression. Heritability was estimated from twin data and from entire pedigree data. RESULTS Internal consistency of all tests was moderate to high (median = 0.86). Effects of gender, age, and education on cognitive performance closely resembled U.S. SAMPLES The CNB-based common factor was completely captured by the WAIS-based g. Some domains, like nonverbal reasoning accuracy, peaked in young adulthood and showed steady decline. Other domains, like language reasoning accuracy, peaked in middle adulthood and were spared decline. CNB-test heritabilities were moderate (median h2 = 31%). Heritability of the CNB common factor was 70%, similar to the WAIS-based g-factor. CONCLUSION The CNB can be used to assess specific neurocognitive performance, as well as to obtain a reliable proxy of general intelligence. Effects of aging and heritability differed across cognitive domains.

Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

Multiple inquiries into the genetic etiology of human traits indicated an overlap between genes underlying monogenic disorders (eg, skeletal growth defects) and those affecting continuous variability of related quantitative traits (eg, height). Extending the idea of a shared genetic basis between a Mendelian disorder and a classic polygenic trait, we performed an association study to examine the effect of 43 genes implicated in autosomal recessive cognitive disorders on intelligence in an unselected Dutch population (N=1316). Using both single-nucleotide polymorphism (SNP)- and gene-based association testing, we detected an association between intelligence and the genes of interest, with genes ELP2, TMEM135, PRMT10, and RGS7 showing the strongest associations. This is a demonstration of the relevance of genes implicated in monogenic disorders of intelligence to normal-range intelligence, and a corroboration of the utility of employing knowledge on monogenic disorders in identifying the genetic variability underlying complex traits.

Association between structural brain network efficiency and intelligence increases during adolescence

Adolescence represents an important period during which considerable changes in the brain take place, including increases in integrity of white matter bundles, and increasing efficiency of the structural brain network. A more efficient structural brain network has been associated with higher intelligence. Whether development of structural network efficiency is related to intelligence, and if so to which extent genetic and environmental influences are implicated in their association, is not known. In a longitudinal study, we mapped FA‐weighted efficiency of the structural brain network in 310 twins and their older siblings at an average age of 10, 13, and 18 years. Age‐trajectories of global and local FA‐weighted efficiency were related to intelligence. Contributions of genes and environment were estimated using structural equation modeling. Efficiency of brain networks changed in a non‐linear fashion from childhood to early adulthood, increasing between 10 and 13 years, and leveling off between 13 and 18 years. Adolescents with higher intelligence had higher global and local network efficiency. The dependency of FA‐weighted global efficiency on IQ increased during adolescence (rph=0.007 at age 10; 0.23 at age 18). Global efficiency was significantly heritable during adolescence (47% at age 18). The genetic correlation between intelligence and global and local efficiency increased with age; genes explained up to 87% of the observed correlation at age 18. In conclusion, the brains structural network differentiates depending on IQ during adolescence, and is under increasing influence of genes that are also associated with intelligence as it develops from late childhood to adulthood.

Genetic Influences on the Development of Cerebral Cortical Thickness During Childhood and Adolescence in a Dutch Longitudinal Twin Sample : The Brainscale Study

&NA; Previous studies have demonstrated that cortical thickness (CT) is under strong genetic control across the life span. However, little is known about genetic influences that cause changes in cortical thickness (&Dgr;CT) during brain development. We obtained 482 longitudinal MRI scans at ages 9, 12, and 17 years from 215 twins and applied structural equation modeling to estimate genetic influences on (1) cortical thickness between regions and across time, and (2) changes in cortical thickness between ages. Although cortical thickness is largely mediated by the same genetic factor throughout late childhood and adolescence, we found evidence for influences of distinct genetic factors on regions across space and time. In addition, we found genetic influences for cortical thinning during adolescence that is mostly due to fluctuating influences from the same genetic factor, with evidence of local influences from a second emerging genetic factor. This fluctuating core genetic factor and emerging novel genetic factor might be implicated in the rapid cognitive and behavioral development during childhood and adolescence, and could potentially be targets for investigation into the manifestation of psychiatric disorders that have their origin in childhood and adolescence.

No Evidence of Causal Effects of Blood Pressure on Cognition in the Population at Large

The large body of literature on the association between blood pressure (BP) and cognitive functioning has yielded mixed results, possibly due to the presence of non-linear effects across age, or because BP affects specific brain areas differently, impacting more on some cognitive skills than on others. If a robust association was detected among BP and specific cognitive tasks, the causal nature of reported associations between BP and cognition could be investigated in twin data, which allow a test of alternative explanations, including genetic pleiotropy. The present study first examines the association between BP and cognition in a sample of 1,140 participants with an age range between 10 and 86 years. Linear and quadratic effects of systolic BP (SBP) and diastolic BP (DBP) on cognitive functioning were examined for 17 tests across five functions. Associations were corrected for effects of sex and linear and quadratic effects of age. Second, to test a causal model, data from 123 monozygotic (MZ) twin pairs were analyzed to test whether cognitive functioning of the twins with the higher BP was different from that of the co-twins with lower BP. Associations between BP and cognitive functioning were absent for the majority of the cognitive tests, with the exception of a lower speed of emotion identification and verbal reasoning in subjects with high diastolic BP. In the MZ twin pair analyses, no effects of BP on cognition were found. We conclude that in the population at large, BP level is not associated with cognitive functioning in a clinically meaningful way.