The role of TREM2 in Alzheimer's disease; evidence from transgenic mouse models.

Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder. Several genetic studies have identified a rare variant of triggering receptor expressed on myeloid cells 2 (TREM2) as a risk factor for AD. TREM2 is thought to trigger the microglial response to amyloid plaques. Mouse models have helped elucidate mechanisms through which TREM2 affects microglial function and modulates pathological features of AD. A synthesis of the 35 mouse-model studies included in this review indicates that TREM2 modulates amyloid plaque composition and deposition, microglial morphology and proliferation, neuroinflammation, and tau phosphorylation. TREM2 also acts as a sensor for anionic lipids exposed during neuronal apoptosis and Aß deposition, may improve spatial abilities and memory, and protect against apoptosis. In early stages of AD, TREM2 knock-down reduces expression of proinflammatory cytokines and upregulates anti-inflammatory cytokines but in later stages, TREM2 may contribute to the disease by aggravating neuroinflammation. The results provide insight into TREM2-related mechanisms that may be associated with AD in humans and may aid future development of disease-modifying pharmacological treatments targeting TREM2.

The nature of the association between number line and mathematical performance: An international twin study.

BACKGROUND: The number line task assesses the ability to estimate numerical magnitudes. People vary greatly in this ability, and this variability has been previously associated with mathematical skills. However, the sources of individual differences in number line estimation and its association with mathematics are not fully understood. AIMS: This large-scale genetically sensitive study uses a twin design to estimate the magnitude of the effects of genes and environments on: (1) individual variation in number line estimation and (2) the covariation of number line estimation with mathematics. SAMPLES: We used over 3,000 8- to 16-year-old twins from the United States, Canada, the United Kingdom, and Russia, and a sample of 1,456 8- to 18-year-old singleton Russian students. METHODS: Twins were assessed on: (1) estimation of numerical magnitudes using a number line task and (2) two mathematics components: fluency and problem-solving. RESULTS: Results suggest that environments largely drive individual differences in number line estimation. Both genes and environments contribute to different extents to the number line estimation and mathematics correlation, depending on the sample and mathematics component. CONCLUSIONS: Taken together, the results suggest that in more heterogeneous school settings, environments may be more important in driving variation in number line estimation and its association with mathematics, whereas in more homogeneous school settings, genetic effects drive the covariation between number line estimation and mathematics. These results are discussed in the light of development and educational settings.

Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression.

Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large-scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi-class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene-network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Transcriptome analysis of genes and gene networks involved in aggressive behavior in mouse and zebrafish.

Despite moderate heritability estimates, the molecular architecture of aggressive behavior remains poorly characterized. This study compared gene expression profiles from a genetic mouse model of aggression with zebrafish, an animal model traditionally used to study aggression. A meta-analytic, cross-species approach was used to identify genomic variants associated with aggressive behavior. The Rankprod algorithm was used to evaluated mRNA differences from prefrontal cortex tissues of three sets of mouse lines (N = 18) selectively bred for low and high aggressive behavior (SAL/LAL, TA/TNA, and NC900/NC100). The same approach was used to evaluate mRNA differences in zebrafish (N = 12) exposed to aggressive or non-aggressive social encounters. Results were compared to uncover genes consistently implicated in aggression across both studies. Seventy-six genes were differentially expressed (PFP < 0.05) in aggressive compared to non-aggressive mice. Seventy genes were differentially expressed in zebrafish exposed to a fight encounter compared to isolated zebrafish. Seven genes (Fos, Dusp1, Hdac4, Ier2, Bdnf, Btg2, and Nr4a1) were differentially expressed across both species 5 of which belonging to a gene-network centred on the c-Fos gene hub. Network analysis revealed an association with the MAPK signaling cascade. In human studies HDAC4 haploinsufficiency is a key genetic mechanism associated with brachydactyly mental retardation syndrome (BDMR), which is associated with aggressive behaviors. Moreover, the HDAC4 receptor is a drug target for valproic acid, which is being employed as an effective pharmacological treatment for aggressive behavior in geriatric, psychiatric, and brain-injury patients. © 2016 Wiley Periodicals, Inc.

Why does parental language input style predict child language development? A twin study of gene-environment correlation.

UNLABELLED: There are well-established correlations between parental input style and child language development, which have typically been interpreted as evidence that the input style causes, or influences the rate of, changes in child language. We present evidence from a large twin study (TEDS; 8395 pairs for this report) that there are also likely to be both child-to-parent effects and shared genetic effects on parent and child. Self-reported parental language style at child age 3 and age 4 was aggregated into an 'informal language stimulation' factor and a 'corrective feedback' factor at each age; the former was positively correlated with child language concurrently and longitudinally at 3, 4, and 4.5 years, whereas the latter was weakly and negatively correlated. Both parental input factors were moderately heritable, as was child language. Longitudinal bivariate analysis showed that the correlation between the language stimulation factor and child language was significantly and moderately due to shared genes. There is some suggestive evidence from longitudinal phenotypic analysis that the prediction from parental language stimulation to child language includes both evocative and passive gene-environment correlation, with the latter playing a larger role. LEARNING OUTCOMES: The reader will understand why correlations between parental language and rate of child language are by themselves ambiguous, and how twin studies can clarify the relationship. The reader will also understand that, based on the present study, at least two aspects of parental language style - informal language stimulation and corrective feedback - have substantial genetic influence, and that for informal language stimulation, a substantial portion of the prediction to child language represents the effect of shared genes on both parent and child. It will also be appreciated that these basic research findings do not imply that parental language input style is unimportant or that interventions cannot be effective.

A systematic review of attention deficit hyperactivity disorder (ADHD) and mathematical ability: current findings and future implications.

BACKGROUND: Several recent behavioural and behavioural genetic studies have investigated the relationship between attention deficit hyperactivity disorder (ADHD) and mathematical ability. The aim of this systematic review was to provide an overview of these studies to date. An emphasis was placed on reviewing results that explored the association between mathematics and the two ADHD components of attention and hyperactivity-impulsivity separately. METHODS: A systematic search of quantitative studies investigating the association between mathematics and ADHD was conducted across five databases (PsychINFO, Web of Science, PubMed, EMBASE, and Scopus). A total of 30 cross-sectional and four longitudinal studies were included in this review. RESULTS: Narrative synthesis of the results was provided using PRISMA guidelines. Taken together, the studies pointed at substantial evidence for a negative association between ADHD symptoms and mathematical ability. This association was particularly marked for the inattentive component of ADHD than for the hyperactive-impulsive component. Evidence from twin studies also showed a significant genetic correlation between mathematics and ADHD, which was greater for the inattentive component of ADHD compared to the hyperactive-impulsive component. CONCLUSIONS: The differential relationship of the hyperactivity-impulsivity and inattention domains with mathematics emphasises the heterogeneity within the disorder and suggests a partially different aetiology of the two ADHD domains. A better understanding of the aetiology of ADHD could help develop more efficient interventions aimed at the reduction of its symptoms. It could also offer an explanatory framework for shortcomings in achievement and inform the development of non-pharmacological intervention strategies.

Pervasive and opposing effects of Unpredictable Chronic Mild Stress (UCMS) on hippocampal gene expression in BALB/cJ and C57BL/6J mouse strains.

BACKGROUND: BALB/cJ is a strain susceptible to stress and extremely susceptible to a defective hedonic impact in response to chronic stressors. The strain offers much promise as an animal model for the study of stress related disorders. We present a comparative hippocampal gene expression study on the effects of unpredictable chronic mild stress on BALB/cJ and C57BL/6J mice. Affymetrix MOE 430 was used to measure hippocampal gene expression from 16 animals of two different strains (BALB/cJ and C57BL/6J) of both sexes and subjected to either unpredictable chronic mild stress (UCMS) or no stress. Differences were statistically evaluated through supervised and unsupervised linear modelling and using Weighted Gene Coexpression Network Analysis (WGCNA). In order to gain further understanding into mechanisms related to stress response, we cross-validated our results with a parallel study from the GENDEP project using WGCNA in a meta-analysis design. RESULTS: The effects of UCMS are visible through Principal Component Analysis which highlights the stress sensitivity of the BALB/cJ strain. A number of genes and gene networks related to stress response were uncovered including the Creb1 gene. WGCNA and pathway analysis revealed a gene network centered on Nfkb1. Results from the meta-analysis revealed a highly significant gene pathway centred on the Ubiquitin C (Ubc) gene. All pathways uncovered are associated with inflammation and immune response. CONCLUSIONS: The study investigated the molecular mechanisms underlying the response to adverse environment in an animal model using a GxE design. Stress-related differences were visible at the genomic level through PCA analysis highlighting the high sensitivity of BALB/cJ animals to environmental stressors. Several candidate genes and gene networks reported are associated with inflammation and neurogenesis and could serve to inform candidate gene selection in human studies and provide additional insight into the pathology of Major Depressive Disorder.

Cross-cultural investigation into cognitive underpinnings of individual differences in early arithmetic.

The present study evaluated 626 5-7-year-old children in the UK, China, Russia, and Kyrgyzstan on a cognitive test battery measuring: (1) general skills; (2) non-symbolic number sense; (3) symbolic number understanding; (4) simple arithmetic - operating with numbers; and (5) familiarity with numbers. Although most inter-population differences were small, 13% of the variance in arithmetic skills could be explained by the sample, replicating the pattern, previously found with older children in PISA. Furthermore, the same cognitive skills were related to early arithmetic in these diverse populations. Only understanding of symbolic number explained variation in mathematical performance in all samples. We discuss the results in terms of potential influences of socio-demographic, linguistic and genetic factors on individual differences in mathematics.

Genes and gene networks implicated in aggression related behaviour.

Aggressive behaviour is a major cause of mortality and morbidity. Despite of moderate heritability estimates, progress in identifying the genetic factors underlying aggressive behaviour has been limited. There are currently three genetic mouse models of high and low aggression created using selective breeding. This is the first study to offer a global transcriptomic characterization of the prefrontal cortex across all three genetic mouse models of aggression. A systems biology approach has been applied to transcriptomic data across the three pairs of selected inbred mouse strains (Turku Aggressive (TA) and Turku Non-Aggressive (TNA), Short Attack Latency (SAL) and Long Attack Latency (LAL) mice and North Carolina Aggressive (NC900) and North Carolina Non-Aggressive (NC100)), providing novel insight into the neurobiological mechanisms and genetics underlying aggression. First, weighted gene co-expression network analysis (WGCNA) was performed to identify modules of highly correlated genes associated with aggression. Probe sets belonging to gene modules uncovered by WGCNA were carried forward for network analysis using ingenuity pathway analysis (IPA). The RankProd non-parametric algorithm was then used to statistically evaluate expression differences across the genes belonging to modules significantly associated with aggression. IPA uncovered two pathways, involving NF-kB and MAPKs. The secondary RankProd analysis yielded 14 differentially expressed genes, some of which have previously been implicated in pathways associated with aggressive behaviour, such as Adrbk2. The results highlighted plausible candidate genes and gene networks implicated in aggression-related behaviour.

The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder.

BACKGROUND: Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. METHODS: Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. RESULTS: In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. CONCLUSIONS: Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.

Why do spatial abilities predict mathematical performance?

Spatial ability predicts performance in mathematics and eventual expertise in science, technology and engineering. Spatial skills have also been shown to rely on neuronal networks partially shared with mathematics. Understanding the nature of this association can inform educational practices and intervention for mathematical underperformance. Using data on two aspects of spatial ability and three domains of mathematical ability from 4174 pairs of 12-year-old twins, we examined the relative genetic and environmental contributions to variation in spatial ability and to its relationship with different aspects of mathematics. Environmental effects explained most of the variation in spatial ability (~70%) and in mathematical ability (~60%) at this age, and the effects were the same for boys and girls. Genetic factors explained about 60% of the observed relationship between spatial ability and mathematics, with a substantial portion of the relationship explained by common environmental influences (26% and 14% by shared and non-shared environments respectively). These findings call for further research aimed at identifying specific environmental mediators of the spatial-mathematics relationship.

Integrative mouse and human mRNA studies using WGCNA nominates novel candidate genes involved in the pathogenesis of major depressive disorder.

AIM: This study aims to identify novel genes associated with major depressive disorder and pharmacological treatment response using animal and human mRNA studies. MATERIALS & METHODS: Weighted gene coexpression network analysis was used to uncover genes associated with stress factors in mice and to inform mRNA probe set selection in a post-mortem study of depression. RESULTS: A total of 171 genes were found to be differentially regulated in response to both early and late stress protocols in a mouse study. Ten human genes, orthologous to mouse genes differentially expressed by stress, were also found to be dysregulated in depressed cases in a human post-mortem brain study from the Stanley Foundation Brain Collection. CONCLUSION: Several novel genes associated with depression were uncovered, including NOVA1 and USP9X. Moreover, we found further evidence in support of hippocampal neurogenesis and peripheral inflammation in major depressive disorder.