Mouse models for psychiatric disorders

Genes involved in psychiatric disorders are difficult to identify, and those that have been proposed so far remain ambiguous. As it is unrealistic to expect the development of, say, a ‘schizophrenic’ or ‘autistic’ mouse, mice are unlikely to have the same role in gene identification in psychiatry as circling mice did in the discovery of human deafness genes. However, many psychiatric disorders are associated with intermediate phenotypes that can be modeled and studied in mice, including physiological or anatomical brain changes and behavioral traits. Mouse models help to evaluate the effect of a human candidate gene mutation on an intermediate trait, and to identify new candidate genes. Once a gene or pathway has been identified, mice are also used to study the interplay of different genes in that system.     

Genetics and genomics of behavioral and psychiatric disorders

Psychiatric conditions are to some degree under genetic influences. Despite the application of advanced genetic and molecular biological technologies, the genetic bases of the human behavioral traits and psychiatric diseases remains largely unresolved. Conventional genetic linkage approaches have not yielded definitive results, possibly because of the absence of objective diagnostic tests, the complex nature of human behavior or the incomplete penetrance of psychiatric traits. However, recent studies have revealed some genes of interest using multifaceted approaches to overcome these challenges. The approaches include using families in which specific behaviors segregate as a mendelian trait, utilization of endophenotypes as biological intermediate traits, identification of psychiatric disease phenotypes in genomic disorders, and the establishment of mouse models.     

Gene–environment interactions at the FKBP5 locus: sensitive periods,mechanisms and pleiotropism

Psychiatric phenotypes are multifactorial and polygenic, resulting from the complex interplay of genes and environmental factors that act cumulatively throughout an organism's lifetime. Adverse life events are strong predictors of risk for a number of psychiatric disorders and a number of studies have focused on gene–environment interactions (GxEs) occurring at genetic loci involved in the stress response. Such a locus that has received increasing attention is the gene encoding FK506 binding protein 51 (FKBP5), a heat shock protein 90 cochaperone of the steroid receptor complex that among other functions regulates sensitivity of the glucocorticoid receptor. Interactions between FKBP5 gene variants and life stressors alter the risk not only for mood and anxiety disorders, but also for a number of other disease phenotypes. In this review, we will focus on molecular and system‐wide mechanisms of this GxE with the aim of establishing a framework that explains GxE interactions. We will also discuss how an understanding of the biological effects of this GxE may lead to novel therapeutic approaches .     

New insights from the last decade of research in psychiatric genetics: discoveries,challenges and clinical implications

Psychiatric genetics has made substantial progress in the last decade, providing new insights into the genetic etiology of psychiatric disorders, and paving the way for precision psychiatry, in which individual genetic profiles may be used to personalize risk assessment and inform clinical decision-making. Long recognized to be heritable, recent evidence shows that psychiatric disorders are influenced by thousands of genetic variants acting together. Most of these variants are commonly occurring, meaning that every individual has a genetic risk to each psychiatric disorder, from low to high. A series of large-scale genetic studies have discovered an increasing number of common and rare genetic variants robustly associated with major psychiatric disorders. The most convincing biological interpretation of the genetic findings implicates altered synaptic function in autism spectrum disorder and schizophrenia. However, the mechanistic understanding is still incomplete. In line with their extensive clinical and epidemiological overlap, psychiatric disorders appear to exist on genetic continua and share a large degree of genetic risk with one another. This provides further support to the notion that current psychiatric diagnoses do not represent distinct pathogenic entities, which may inform ongoing attempts to reconceptualize psychiatric nosology. Psychiatric disorders also share genetic influences with a range of behavioral and somatic traits and diseases, including brain structures, cognitive function, immunological phenotypes and cardiovascular disease, suggesting shared genetic etiology of potential clinical importance. Current polygenic risk score tools, which predict individual genetic susceptibility to illness, do not yet provide clinically actionable information. However, their precision is likely to improve in the coming years, and they may eventually become part of clinical practice, stressing the need to educate clinicians and patients about their potential use and misuse. This review discusses key recent insights from psychiatric genetics and their possible clinical applications, and suggests future directions.     

The challenges and promise of neuroimaging in psychiatry

Neuroimaging is central to the quest for a biological foundation of psychiatric diagnosis but so far has not yielded clinically relevant biomarkers for mental disorders. This review addresses potential reasons for this limitation and discusses refinements of paradigms and analytic techniques that may yield improved diagnostic and prognostic accuracy. Neuroimaging can also be used to probe genetically defined biological pathways underlying mental disorders, for example through the genetic imaging of variants discovered in genome-wide association studies. These approaches may ultimately reveal mechanisms through which genes contribute to psychiatric symptoms and how pharmacological and psychological interventions exert their effects.     

When brain clocks lose track of time: cause or consequence of neuropsychiatric disorders

Patients suffering from neuropsychiatric disorders often exhibit a loss of regulation of their biological rhythms which leads to altered sleep/wake cycle, body temperature rhythm and hormonal rhythms. Whereas these symptoms have long been considered to result from the pathology of the underlying disease, increasing evidence now indicates that the circadian system may be more directly involved in the etiology of psychiatric disorders. This emerging view originated with the discovery that the genes involved in the generation of biological rhythms are expressed in many brain structures where clocks function-and perhaps malfunction. It is also due to the interesting phenotypes of clock mutant mice. Here we summarize recent reports showing that alteration of circadian clocks within key brain regions associated with neuropsychiatric disorders may be an underlying cause of the development of mental illness. We discuss how these alterations take place at both systems and molecular levels.     

Shared genetic risk factors for obstructive sleep apnea and obesity.

Both obesity and obstructive sleep apnea (OSA) are complex disorders with multiple risk factors, which interact in a complicated fashion to determine the overall phenotype. In addition to environmental risk factors, each disorder has a strong genetic basis that is likely due to the summation of small to moderate effects from a large number of genetic loci. Obesity is a strong risk factor for sleep apnea, and there are some data to suggest sleep apnea may influence obesity. It is therefore not surprising that many susceptibility genes for obesity and OSA should be shared. Current research suggests that approximately half of the genetic variance in the apnea hypopnea index is shared with obesity phenotypes. Genetic polymorphisms that increase weight will also be risk factors for apnea. In addition, given the interrelated pathways regulating both weight and other intermediate phenotypes for sleep apnea such as ventilatory control, upper airway muscle function, and sleep characteristics, it is likely that there are genes with pleiotropic effects independently impacting obesity and OSA traits. Other genetic loci likely interact with obesity to influence development of OSA in a gene-by-environment type of effect. Conversely, environmental stressors such as intermittent hypoxia and sleep fragmentation produced by OSA may interact with obesity susceptibility genes to modulate the importance that these loci have on defining obesity-related traits.     

Metabolic network analysis revealed distinct routes of deletion effects between essential and non-essential genes

Interest in essential genes has arisen recently given their importance in antimicrobial drug development. Although knockouts of essential genes are commonly known to cause lethal phenotypes, there is insufficient understanding on the intermediate changes followed by genetic perturbation and to what extent essential genes correlate to other genes. Here, we characterized the gene knockout effects by using a list of affected genes, termed as 'damage lists'. These damage lists were identified through a refined cascading failure approach that was based on a previous topological flux balance analysis. Using an Escherichia coli metabolic network, we incorporated essentiality information into damage lists and revealed that the knockout of an essential gene mainly affects a large range of other essential genes whereas knockout of a non-essential gene only interrupts other non-essential genes. Also, genes sharing common damage lists tend to have the same essentiality. We extracted 72 core functional modules from the common damage lists of essential genes and demonstrated their ability to halt essential metabolites production. Overall, our network analysis revealed that essential and non-essential genes propagated their deletion effects via distinct routes, conferring mechanistic explanation to the observed lethality phenotypes of essential genes.     

Genetic insights into the functional elements of language

Language disorders cover a wide range of conditions with heterologous and overlapping phenotypes and complex etiologies harboring both genetic and environmental influences. Genetic approaches including the identification of genes linked to speech and language phenotypes and the characterization of normal and aberrant functions of these genes have, in recent years, unraveled complex details of molecular and cognitive mechanisms and provided valuable insight into the biological foundations of language. Consistent with this approach, we have reviewed the functional aspects of allelic variants of genes which are currently known to be either causally associated with disorders of speech and language or impact upon the spectrum of normal language ability. We have also reviewed candidate genes associated with heritable speech and language disorders. In addition, we have evaluated language phenotypes and associated genetic components in developmental syndromes that, together with a spectrum of altered language abilities, manifest various phenotypes and offer details of multifactorial determinants of language function. Data from this review have revealed a predominance of regulatory networks involved in the control of differentiation and functioning of neurons, neuronal tracks and connections among brain structures associated with both cognitive and language faculties. Our findings, furthermore, have highlighted several multifactorial determinants in overlapping speech and language phenotypes. Collectively this analysis has revealed an interconnected developmental network and a close association of the language faculty with cognitive functions, a finding that has the potential to provide insight into linguistic hypotheses defining in particular, the contribution of genetic elements to and the modular nature of the language faculty.     

When clocks go bad: neurobehavioural consequences of disrupted circadian timing

Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain’s critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.     

Postprandial lipoprotein metabolism, genes and risk of cardiovascular disease

PURPOSE OF REVIEW: Several lines of evidence suggest that postprandial lipemia increases the risk of atherogenesis, and in each of the systems involved in postprandial metabolism the roles of many genes have been explored in order to establish the possible implications of their variability in coronary heart disease risk. RECENT FINDINGS: This report focuses on recent results pertaining to postprandial lipoprotein metabolism and genes, their variability and their relationship with intermediate phenotypes and coronary heart disease. The postprandial lipid response was modified by polymorphisms within the genes for apolipoprotein AI, apolipoprotein E, apolipoprotein B, apolipoprotein CI, apolipoprotein CIII, apolipoprotein AIV, apolipoprotein AV, lipoprotein lipase, hepatic lipase, fatty acid-binding protein-2, the fatty acid transport proteins, microsomal triglyceride transfer protein and scavenger receptor class B type I. We also discuss recent advances in the effects of gene regulation using knockdown animal models on postprandial lipoprotein metabolism. SUMMARY: The review discusses several of these factors as well as the potential impact of gene polymorphism on the variability of postprandial lipoprotein metabolism as intermediate phenotypes for coronary heart disease. The variability in postprandial lipid response is highly complex. Future studies will need to be large if they are to assess the effects of multiple polymorphisms.     

A network of genes, genetic disorders, and brain areas

The network-based approach has been used to describe the relationship among genes and various phenotypes, producing a network describing complex biological relationships. Such networks can be constructed by aggregating previously reported associations in the literature from various databases. In this work, we applied the network-based approach to investigate how different brain areas are associated to genetic disorders and genes. In particular, a tripartite network with genes, genetic diseases, and brain areas was constructed based on the associations among them reported in the literature through text mining. In the resulting network, a disproportionately large number of gene-disease and disease-brain associations were attributed to a small subset of genes, diseases, and brain areas. Furthermore, a small number of brain areas were found to be associated with a large number of the same genes and diseases. These core brain regions encompassed the areas identified by the previous genome-wide association studies, and suggest potential areas of focus in the future imaging genetics research. The approach outlined in this work demonstrates the utility of the network-based approach in studying genetic effects on the brain.     

Perturbateurs endocriniens et troubles du comportement

Prenatal environmental events that disturb neurodevelopment are suspected to increase the risk of psychiatric disorders. Estrogenic hormones such as diethylstilbestrol (DES) and environmental monomers like Bisphenol A (BPA) have the potential to disturb the development of the foetus and especially its brain. We reviewed the epidemiological studies investigating a possible association between prenatal DES or BPA exposure and risk of psychiatric disorders and discussed the hypothetical biological mechanisms linking this prenatal exposure with psychiatric disorders. The principal methodological issues that could represent confounding factors and may explain conflicting results are discussed. Interestingly, prenatal exposure to DES and BPA has been linked to epigenetic alterations associated with urogenital lesions observed in the exposed offspring, supporting the hypothesis that this environmental factor can indeed alter epigenetic regulations. Following the same line of thinking, these endocrine disruptors may modify the epigenetic mechanisms involved in neurodevelopment and, in turn, increase the occurrence of psychiatric disorders.     

Neuronal cell adhesion genes

The major mental disorders, schizophrenia and bipolar disorder are substantially heritable. Recent genomic studies have identified a small number of common and rare risk genes contributing to both disorders and support epidemiological evidence that genetic susceptibility overlaps between them. Prompted by the question of whether risk genes cluster in specific molecular pathways or implicate discrete mechanisms we and others have developed hypothesis-free methods of investigating genome-wide association datasets at a pathway-level. The application of our method to the 212 experimentally-derived pathways in the Kyoto Encycolpaedia of Genes and Genomes (KEGG) database identified significant association between the cell adhesion molecule (CAM) pathway and both schizophrenia and bipolar disorder susceptibility across three GWAS datasets. Interestingly, a similar approach applied to an autistic spectrum disorders (ASDs) sample identified a similar pathway and involved many of the same genes. Disruption of a number of these genes (including NRXN1, CNTNAP2 and CASK) are known to cause diverse neurodevelopmental brain disorder phenotypes including schizophenia, autism, learning disability and specific language disorder. Taken together these studies bring the CAM pathway sharply into focus for more comprehensive DNA sequencing to identify the critical genes, and investigate their relationships and interaction with environmental risk factors in the expression of many seemingly different neurodevelopmental disorders.     

A Simple Cell-Based Assay Reveals That Diverse Neuropsychiatric Risk Genes Converge on Primary Cilia

Human genetic studies are beginning to identify a large number of genes linked to neuropsychiatric disorders. It is increasingly evident that different genes contribute to risk for similar syndromes and, conversely, the same genes or even the same alleles cross over traditional diagnostic categories. A current challenge is to understand the cellular biology of identified risk genes. However, most genes associated with complex neuropsychiatric phenotypes are not related through a known biochemical pathway, and many have an entirely unknown cellular function. One possibility is that diverse disease-linked genes converge at a higher-level cellular structure. The synapse is already known to be one such convergence, and emerging evidence suggests the primary cilium as another. Because many genes associated with neuropsychiatric illness are expressed also outside the nervous system, as are cilia, we tested the hypothesis that such genes affect conserved features of the primary cilium. Using RNA interference to test 41 broadly expressed candidate genes associated with schizophrenia, bipolar affective disorder, autism spectrum disorder and intellectual disability, we found 20 candidates that reduce ciliation in NIH3T3 cells when knocked down, and three whose manipulation increases cilia length. Three of the candidate genes were previously implicated in cilia formation and, altogether, approximately half of the candidates tested produced a ciliary phenotype. Our results support the hypothesis that primary cilia indeed represent a conserved cellular structure at which the effects of diverse neuropsychiatric risk genes converge. More broadly, they suggest a relatively simple cell-based approach that may be useful for exploring the complex biological underpinnings of neuropsychiatric disease.     

Strategies for performing genotype–phenotype association studies in nonhuman primates

Anthropoid primate models offer opportunities to study genetic influence on alcohol consumption and alcohol-related intermediate phenotypes in socially and behaviorally complex animal models that are closely related to humans, and in which functionally equivalent or orthologous genetic variants exist. This review will discuss the methods commonly used for performing candidate gene-based studies in rhesus macaques in order to model how functional genetic variation moderates risk for human psychiatric disorders. Various in silico and in vitro approaches to identifying functional genetic variants for performance of these studies will be discussed. Next, I will provide examples of how this approach can be used for performing candidate gene-based studies and for examining gene by environment interactions. Finally, these approaches will then be placed in the context of how function-guided studies can inform us of genetic variants that may be under selection across species, demonstrating how functional genetic variants that may have conferred selective advantage at some point in the evolutionary history of humans could increase risk for addictive disorders in modern society.     

Epigenetic regulation in psychiatric disorders

Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.     

Characterization of lamin mutation phenotypes in Drosophila and comparison to human laminopathies

Lamins are intermediate filament proteins that make up the nuclear lamina, a matrix underlying the nuclear membrane in all metazoan cells that is important for nuclear form and function. Vertebrate A-type lamins are expressed in differentiating cells, while B-type lamins are expressed ubiquitously. Drosophila has two lamin genes that are expressed in A- and B-type patterns, and it is assumed that similarly expressed lamins perform similar functions. However, Drosophila and vertebrate lamins are not orthologous, and their expression patterns evolved independently. It is therefore of interest to examine the effects of mutations in lamin genes. Mutations in the mammalian lamin A/C gene cause a range of diseases, collectively called laminopathies, that include muscular dystrophies and premature aging disorders. We compared the sequences of lamin genes from different species, and we have characterized larval and adult phenotypes in Drosophila bearing mutations in the lam gene that is expressed in the B-type pattern. Larvae move less and show subtle muscle defects, and surviving lam adults are flightless and walk like aged wild-type flies, suggesting that lam phenotypes might result from neuromuscular defects, premature aging, or both. The resemblance of Drosophila lam phenotypes to human laminopathies suggests that some lamin functions may be performed by differently expressed genes in flies and mammals. Such still-unknown functions thus would not be dependent on lamin gene expression pattern, suggesting the presence of other lamin functions that are expression dependent. Our results illustrate a complex interplay between lamin gene expression and function through evolution.     

Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules

Intellectual disability (ID) disorders are genetically and phenotypically extremely heterogeneous. Can this complexity be depicted in a comprehensive way as a means of facilitating the understanding of ID disorders and their underlying biology? We provide a curated database of 746 currently known genes, mutations in which cause ID (ID-associated genes [ID-AGs]), classified according to ID manifestation and associated clinical features. Using this integrated resource, we show that ID-AGs are substantially enriched with co-expression, protein-protein interactions, and specific biological functions. Systematic identification of highly enriched functional themes and phenotypes revealed typical phenotype combinations characterizing process-defined groups of ID disorders, such as chromatin-related disorders and deficiencies in DNA repair. Strikingly, phenotype classification efficiently breaks down ID-AGs into subsets with significantly elevated biological coherence and predictive power. Custom-made functional Drosophila datasets revealed further characteristic phenotypes among ID-AGs and specific clinical classes. Our study and resource provide systematic insights into the molecular and clinical landscape of ID disorders, represent a significant step toward overcoming current limitations in ID research, and prove the utility of systematic human and cross-species phenomics analyses in highly heterogeneous genetic disorders.