Epigenetic differences in monozygotic twins discordant for major depressive disorder

Although monozygotic (MZ) twins share the majority of their genetic makeup, they can be phenotypically discordant on several traits and diseases. DNA methylation is an epigenetic mechanism that can be influenced by genetic, environmental and stochastic events and may have an important impact on individual variability. In this study we explored epigenetic differences in peripheral blood samples in three MZ twin studies on major depressive disorder (MDD). Epigenetic data for twin pairs were collected as part of a previous study using 8.1-K-CpG microarrays tagging DNA modification in white blood cells from MZ twins discordant for MDD. Data originated from three geographical regions: UK, Australia and the Netherlands. Ninety-seven MZ pairs (194 individuals) discordant for MDD were included. Different methods to address non independently-and-identically distributed (non-i.i.d.) data were evaluated. Machine-learning methods with feature selection centered on support vector machine and random forest were used to build a classifier to predict cases and controls based on epivariations. The most informative variants were mapped to genes and carried forward for network analysis. A mixture approach using principal component analysis (PCA) and Bayes methods allowed to combine the three studies and to leverage the increased predictive power provided by the larger sample. A machine-learning algorithm with feature reduction classified affected from non-affected twins above chance levels in an independent training-testing design. Network analysis revealed gene networks centered on the PPAR-γ (NR1C3) and C-MYC gene hubs interacting through the AP-1 (c-Jun) transcription factor. PPAR-γ (NR1C3) is a drug target for pioglitazone, which has been shown to reduce depression symptoms in patients with MDD. Using a data-driven approach we were able to overcome challenges of non-i.i.d. data when combining epigenetic studies from MZ twins discordant for MDD. Individually, the studies yielded negative results but when combined classification of the disease state from blood epigenome alone was possible. Network analysis revealed genes and gene networks that support the inflammation hypothesis of MDD

Identification of genes and gene pathways associated with major depressive disorder by integrative brain analysis of rat and human prefrontal cortex transcriptomes

Despite moderate heritability estimates, progress in uncovering the molecular substrate underpinning major depressive disorder (MDD) has been slow. In this study, we used prefrontal cortex (PFC) gene expression from a genetic rat model of MDD to inform probe set prioritization in PFC in a human post-mortem study to uncover genes and gene pathways associated with MDD. Gene expression differences between Flinders sensitive (FSL) and Flinders resistant (FRL) rat lines were statistically evaluated using the RankProd, non-parametric algorithm. Top ranking probe sets in the rat study were subsequently used to prioritize orthologous selection in a human PFC in a case?control post-mortem study on MDD from the Stanley Brain Consortium. Candidate genes in the human post-mortem study were then tested against a matched control sample using the RankProd method. A total of 1767 probe sets were differentially expressed in the PFC between FSL and FRL rat lines at (qless than or equal to0.001). A total of 898 orthologous probe sets was found on Affymetrix?s HG-U95A chip used in the human study. Correcting for the number of multiple, non-independent tests, 20 probe sets were found to be significantly dysregulated between human cases and controls at qless than or equal to0.05. These probe sets tagged the expression profile of 18 human genes (11 upregulated and seven downregulated). Using an integrative rat?human study, a number of convergent genes that may have a role in pathogenesis of MDD were uncovered. Eighty percent of these genes were functionally associated with a key stress response signalling cascade, involving NF-?B (nuclear factor kappa-light-chain-enhancer of activated B cells), AP-1 (activator protein 1) and ERK/MAPK, which has been systematically associated with MDD, neuroplasticity and neurogenesis

The genetic and environmental aetiology of spatial, mathematics and general anxiety

Individuals differ in their level of general anxiety as well as in their level of anxiety towards specific activities, such as mathematics and spatial tasks. Both specific anxieties correlate moderately with general anxiety, but the aetiology of their association remains unexplored. Moreover, the factor structure of spatial anxiety is to date unknown. The present study investigated the factor structure of spatial anxiety, its aetiology, and the origins of its association with general and mathematics anxiety in a sample of 1,464 19-21-year-old twin pairs from the UK representative Twins Early Development Study. Participants reported their general, mathematics and spatial anxiety as part of an online battery of tests. We found that spatial anxiety is a multifactorial construct, including two components: navigation anxiety and rotation/visualization anxiety. All anxiety measures were moderately heritable (30% to 41%), and non-shared environmental factors explained the remaining variance. Multivariate genetic analysis showed that, although some genetic and environmental factors contributed to all anxiety measures, a substantial portion of genetic and non-shared environmental influences were specific to each anxiety construct. This suggests that anxiety is a multifactorial construct phenotypically and aetiologically, highlighting the importance of studying anxiety within specific contexts

Explicit computation of sampling period in periodic event-triggered multi-agent control under limited data rate

This paper investigates the coordination of nonlinear sampled-data multi-agent systems subject to data rate constraint. The purpose is to design resource-efficient communication and control strategies that guarantee exponential synchronization. Two implementation scenarios are considered, the period time-triggered control and the period event-triggered control. One of the main difficulties of the problem is to obtain an explicit formula for the maximum allowable sampling period (MASP). To this end, an approach on finding the MASP for periodic time-triggered control is proposed first. Then, an asynchronous period event-triggered control strategy is formulated, a communication function and a control function are designed for each agent to determine respectively whether or not the sampled data and the control input should be transmitted at each sampling instant. Finally, the constraint of limited data rate is considered. An observer-based encoder-decoder and a finite-level quantizer are designed respectively for the Sensor-Controller communication and the Controller-Actuator communication such that certain constraint on the data rate is satisfied. It is shown that exponential synchronization can still be achieved in the presence of data rate constraint. A simulation example is given to illustrate the effectiveness of the theoretical resultsQC 20191009. QC 20200129</p

The re-emergence of spatial reasoning within primary years mathematics education

This chapter presents a review of the re-emergence of spatial reasoning in Australasia as a potentially powerful but under-utilised bridging mechanism between real-world experiences and mathematics teaching and learning. This is the first time a chapter has been dedicated solely to spatial reasoning in the Mathematics Education Research Group of Australasia’s (MERGA’s) four yearly review and hence the chapter outlines preliminary studies that have formed the basis for the research profiled in the 2016–2019 period. The focus on primary years (Foundation to Year six) mathematics reflects a resurgence of insights from the 1980s amplified as a research focus on the interaction of spatial reasoning and mathematics development during childhood. Because mathematical concept formation is connected to interaction with the three-dimensional world in both a mathematical and non-mathematical way it will be important to spatialise the primary curriculum. The review includes coverage of the work of established Australasian research projects, along with smaller studies and literature emanating from intervention programs that are not nominally spatial, but have spatial underpinnings or spatial reasoning components. While further research is needed to explore teacher knowledge and practice, this chapter acknowledges the valuable contributions and global influence of re-emerging Australasian research