Genetic and Environmental Effects on the Early Motor Development as a Function of Parental Educational Attainment.

INTRODUCTION: The contribution of genetic and environmental factors to individual differences in early motor development is still largely uncharted. This large-scale twin study establishes the genetic and environmental influences on the timing of motor milestones achievement, and it further tests whether the influences are moderated by parental education. METHODS: The twins came from families registered in the Netherlands Twin Register (NTR) from 1986 to 2016. In 30,256 complete twin pairs, mother-reported ages at which each twin was able to first-time roll from back to belly, sit unassisted, hands-and-knees crawl, stand up unaided, and walk independently were used to extract an early motor development factor. Parental education was dichotomized ("both parents with low/average education" vs "at least one parent with high education" with university degree as a threshold). RESULTS: Additive genetics explained 52% of the variance in motor development, the remaining 39% and 9% were explained by shared and nonshared environment separately. Mean age of achieving motor milestones tended to be higher in infants with high educated parents, and a moderation of parental education on the genetic and environmental variance in motor development was seen in female twins with larger heritability in the high educated parents group (64% vs 43%) paired to a lower shared environmental influence (28% vs 48%). Only 7%-8% of the variance was accounted for nonshared environmental factors, including measurement error. The pattern of results did not change when the degree of urbanicity, a correlate of parental education, was additionally considered. CONCLUSIONS: Genetic factors explain most of the individual differences in the timing of motor milestone achievement, but factors related to the shared home environment also play an important role in early motor development.

Measurement and genetic architecture of lifetime depression in the Netherlands as assessed by LIDAS (Lifetime Depression Assessment Self-report).

BACKGROUND: Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression. METHODS: Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS). RESULTS: Estimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15-1.32, R2 = 1.47%). CONCLUSIONS: By assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.

Genetic Similarity Assessment of Twin-Family Populations by Custom-Designed Genotyping Array.

Twin registries often take part in large collaborative projects and are major contributors to genome-wide association (GWA) meta-analysis studies. In this article, we describe genotyping of twin-family populations from Australia, the Midwestern USA (Avera Twin Register), the Netherlands (Netherlands Twin Register), as well as a sample of mothers of twins from Nigeria to assess the extent, if any, of genetic differences between them. Genotyping in all cohorts was done using a custom-designed Illumina Global Screening Array (GSA), optimized to improve imputation quality for population-specific GWA studies. We investigated the degree of genetic similarity between the populations using several measures of population variation with genotype data generated from the GSA. Visualization of principal component analysis (PCA) revealed that the Australian, Dutch and Midwestern American populations exhibit negligible interpopulation stratification when compared to each other, to a reference European population and to globally distant populations. Estimations of fixation indices (FST values) between the Australian, Midwestern American and Netherlands populations suggest minimal genetic differentiation compared to the estimates between each population and a genetically distinct cohort (i.e., samples from Nigeria genotyped on GSA). Thus, results from this study demonstrate that genotype data from the Australian, Dutch and Midwestern American twin-family populations can be reasonably combined for joint-genetic analysis.

Impedance cardiography in healthy children and children with congenital heart disease: Improving stroke volume assessment.

INTRODUCTION: Stroke volume (SV) and cardiac output are important measures in the clinical evaluation of cardiac patients and are also frequently used in research applications. This study was aimed to improve SV scoring derived from spot-electrode based impedance cardiography (ICG) in a pediatric population of healthy volunteers and patients with a corrected congenital heart defect. METHODS: 128 healthy volunteers and 66 patients participated. First, scoring methods for ambiguous ICG signals were optimized to improve agreement of B- and X-points with aortic valve opening/closure in simultaneously recorded transthoracic echocardiography (TTE). Building on the improved scoring of B- and X-points, the Kubicek equation for SV estimation was optimized by testing the agreement with the simultaneously recorded SV by TTE. Both steps were initially done in a subset of the sample of healthy children and then validated in the remaining subset of healthy children and in a sample of patients. RESULTS: SV assessment by ICG in healthy children strongly improved (intra class correlation increased from 0.26 to 0.72) after replacing baseline thorax impedance (Z0) in the Kubicek equation by an equation (7.337-6.208∗dZ/dtmax), where dZ/dtmax is the amplitude of the ICG signal at the C-point. Reliable SV assessment remained more difficult in patients compared to healthy controls. CONCLUSIONS: After proper adjustment of the Kubicek equation, SV assessed by the use of spot-electrode based ICG is comparable to that obtained from TTE. This approach is highly feasible in a pediatric population and can be used in an ambulatory setting.

Temporal stability and drivers of change in cardiac autonomic nervous system activity.

OBJECTIVES: This study determined temporal stability of ambulatory measured cardiac autonomic activity for different time periods and investigated potential drivers of changes in this activity. METHODS: Data was drawn from baseline (n=2379), 2-year (n=2245), and 6-year (n=1876) follow-up from the Netherlands Study of Depression and Anxiety. Cardiac autonomic activity was measured with heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). Autonomic temporal stability was determined across 2, 4, and 6year intervals. We subsequently examined the association between sociodemographics, lifestyle, mental health, cardiometabolic health, and the use of antidepressant and cardiac medication with change in cardiac autonomic activity. RESULTS: Over 2years, stability was good for HR (ICC=0.703), excellent for RSA (ICC=0.792) and moderate for PEP (ICC=0.576). Stability decreased for a 4- (HR ICC=0.688, RSA ICC=0.652 and PEP ICC=0.387) and 6-year interval (HR ICC=0.633, RSA ICC=0.654 and PEP ICC=0.355). The most important determinants for increase in HR were (increase in) smoking, increase in body mass index (BMI) and (starting) the use of antidepressants. Beta-blocking/antiarrhythmic drug use led to a decrease in HR. Decrease in RSA was associated with age, smoking and (starting) antidepressant use. Decrease in PEP was associated with age and (increase in) BMI. CONCLUSIONS: Cardiac autonomic measures were rather stable over 2years, but stability decreased with increasing time span. Determinants contributing to cardiac autonomic deterioration were older age, (increase in) smoking and BMI, and (starting) the use of antidepressants. (Starting) the use of cardiac medication improved autonomic function.

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.

Intrapair differences in hippocampal volume in monozygotic twins discordant for the risk for anxiety and depression.

BACKGROUND: Current biological psychiatric models assume that genetic and environmental risk factors for anxiety and depression act on the same brain structures. METHODS: To test this assumption, we assessed brain anatomy by using optimized voxel-based morphometry on magnetic resonance images obtained in monozygotic twin pairs who were discordant for the risk of anxiety and depression (n = 10 pairs) and in monozygotic twin pairs who were concordant for high (n = 7 pairs) or low (n = 15 pairs) risk for anxiety and depression. RESULTS: We observed volume reductions in the temporal lobe, most notably in the left posterior hippocampal region in subjects at high risk for anxiety and depression, but exclusively in the intrapair comparison of discordant monozygotic twins. Because monozygotic twins are genetically identical, any discordance in their risk for anxiety and depression and hippocampal volume must arise from differential exposure to environmental influences. A group comparison between pairs concordant for low or high risk, which is more likely to reflect differences in genetic vulnerability, did not show reduced temporal-lobe and posterior hippocampal volumes in the pairs at high risk for anxiety and depression. CONCLUSIONS: This pattern of results suggests that damage to temporal-lobe structures may be specific to an environmentally driven etiology of anxiety and depression.