Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment

Purpose: To measure prothrombin fragments (F1+2) and thrombin-antithrombin complex (TAT) in vitreous and subretinal fluid (SRF) of rhegmatogenous retinal detachment (RRD) patients and to validate and further specify our earlier finding of increased thrombin activity in patients with proliferative vitreoretinopathy (PVR). Methods: F1+2 and TAT were measured in 31 vitreous and 16 SRF samples using the Enzygnost® immunoassays. Results: We found significant levels of F1+2 and TAT in the vitreous of all patients with RRD compared to patients with macular hole or macular pucker. However, there was no significant difference between patients who would develop PVR in the future, had established PVR, and patients with uncomplicated RRD both in vitreous concentrations of F1+2 (Kruskal-Wallis p = 0.963) and TAT (p = 0.516). Conclusion: The analysis of F1+2 and TAT confirmed significant thrombin generation in both vitreous and SRF of patients with RRD. An imbalance between the thrombin regulation mechanisms TAT and α2-macroglobulin possibly explains the difference from our previous findings

Heritability of Urinary Amines, Organic Acids, and Steroid Hormones in Children

Variation in metabolite levels reflects individual differences in genetic and environmental factors. Here, we investigated the role of these factors in urinary metabolomics data in children. We examined the effects of sex and age on 86 metabolites, as measured on three metabolomics platforms that target amines, organic acids, and steroid hormones. Next, we estimated their heritability in a twin cohort of 1300 twins (age range: 5.7-12.9 years). We observed associations between age and 50 metabolites and between sex and 21 metabolites. The monozygotic (MZ) and dizygotic (DZ) correlations for the urinary metabolites indicated a role for non-additive genetic factors for 50 amines, 13 organic acids, and 6 steroids. The average broad-sense heritability for these amines, organic acids, and steroids was 0.49 (range: 0.25-0.64), 0.50 (range: 0.33-0.62), and 0.64 (range: 0.43-0.81), respectively. For 6 amines, 7 organic acids, and 4 steroids the twin correlations indicated a role for shared environmental factors and the average narrow-sense heritability was 0.50 (range: 0.37-0.68), 0.50 (range; 0.23-0.61), and 0.47 (range: 0.32-0.70) for these amines, organic acids, and steroids. We conclude that urinary metabolites in children have substantial heritability, with similar estimates for amines and organic acids, and higher estimates for steroid hormones

Urinary amine and organic acid metabolites evaluated as markers for childhood aggression : the ACTION biomarker study

Biomarkers are of interest as potential diagnostic and predictive instruments in personalized medicine. We present the first urinary metabolomics biomarker study of childhood aggression. We aim to examine the association of urinary metabolites and neurotransmitter ratios involved in key metabolic and neurotransmitter pathways in a large cohort of twins (N = 1,347) and clinic-referred children (N = 183) with an average age of 9.7 years. This study is part of ACTION (Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies), in which we developed a standardized protocol for large-scale collection of urine samples in children. Our analytical design consisted of three phases: a discovery phase in twins scoring low or high on aggression (N = 783); a replication phase in twin pairs discordant for aggression (N = 378); and a validation phase in clinical cases and matched twin controls (N = 367). In the discovery phase, 6 biomarkers were significantly associated with childhood aggression, of which the association of O-phosphoserine (beta = 0.36; SE = 0.09; p = 0.004), and gamma-L-glutamyl-L-alanine (beta = 0.32; SE = 0.09; p = 0.01) remained significant after multiple testing. Although non-significant, the directions of effect were congruent between the discovery and replication analyses for six biomarkers and two neurotransmitter ratios and the concentrations of 6 amines differed between low and high aggressive twins. In the validation analyses, the top biomarkers and neurotransmitter ratios, with congruent directions of effect, showed no significant associations with childhood aggression. We find suggestive evidence for associations of childhood aggression with metabolic dysregulation of neurotransmission, oxidative stress, and energy metabolism. Although replication is required, our findings provide starting points to investigate causal and pleiotropic effects of these dysregulations on childhood aggression

A powerful and rapid approach to human genome scanning using small quantities of genomic DNA

Summary Dense maps of short-tandem-repeat polymorphisms (STRPs) have allowed genome-wide searches for genes involved in a great variety of diseases with genetic influences, including common complex diseases. Generally for this purpose, marker sets with a 10 cM spacing are genotyped in hundreds of individuals. We have performed power simulations to estimate the maximum possible intermarker distance that still allows for sufficient power. In this paper we further report on modifications of previously published protocols, resulting in a powerful screening set containing 229 STRPs with an average spacing of 18n3 cM. A complete genome scan using our protocol requires only 80 multiplex PCR reactions which are all carried out using one set of conditions and which do not contain overlapping marker allele sizes. The multiplex PCR reactions are grouped by sets of chromosomes, which enables on-line statistical analysis of a set of chromosomes, as sets of chromosomes are being genotyped. A genome scan following this modified protocol can be performed using a maximum amount of 2n5 µg of genomic DNA per individual, isolated from either blood or from mouth swabs

Genome-wide association of major depression: description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects.

To identify the genomic regions that confer risk and protection for major depressive disorder (MDD) in humans, large-scale studies are needed. Such studies should collect multiple phenotypes, DNA, and ideally, biological material that allows gene expression analysis, transcriptomic, proteomic, and metabolomic studies. In this paper, we briefly review linkage studies of MDD and then describe the large-scale nationwide biological sample collection in Dutch twin families from the Netherlands Twin Register (NTR) and in participants in the Netherlands Study of Depression and Anxiety (NESDA). Within these studies, 1862 participants with a diagnosis of MDD and 1857 controls at low liability for MDD have been selected for genome-wide genotyping by the US Foundation for the National Institutes of Health Genetic Association Information Network. Stage 1 genome-wide association results are scheduled to be accessible before the end of 2007. Genome-wide association results are open-access and can be viewed at the dbGAP web portal (http://www.ncbi.nlm.nih.gov). Approved users can download the genotype and phenotype data, which have been made available as of 9 October 2007

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.</p