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Molecular Psychiatry (2007) 12, 324–330 & 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00 www.nature.com/mp FEATURE REVIEW Genetics of behavioural domains across the neuropsychiatric spectrum; of mice and men MJH Kas1, C Fernandes1,2, LC Schalkwyk2 and DA Collier2 1 Department of Pharmacology and Anatomy, Behavioural Genomics Section, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands and 2King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK Family and twin studies have revealed that genetic factors play a major role in psychiatric disorders, however, attempts to find susceptibility genes for these complex disorders have been largely unsuccessful. Therefore, new research strategies are required to tackle the complex interactions of genes, developmental, and environmental events. Here, we will address a behavioural domain concept that focuses on the genetics of behavioural domains relevant to both animal behaviour and across human psychiatric disorders. We believe that interspecies trait genetics rather than complex syndrome genetics will optimize genotype– phenotype relationships for psychiatric disorders and facilitate the identification of biological substrates underlying these disorders. Molecular Psychiatry (2007) 12, 324–330. doi:10.1038/sj.mp.4001979; published online 21 November 2006 Keywords: psychiatry; animal models; human; endophenotype; behaviour; environment Introduction Genetic factors play a major role in psychiatric disorders: for example, twin studies showed that heritability for schizophrenia is estimated to be > 80%. Identification of susceptibility genes for these complex genetic disorders, which are expected to be composed of many genes of small effect acting together with environmental factors, has been slow and only a handful of genes look more than promising as susceptibility factors; for many disorders, such as anxiety and depression, there has been little progress in the identification of genetic risk factors. Furthermore, the examination of environmental factors and in particular gene–environment interactions and the nature of developmental effects have been difficult to examine in human populations, even with prospectively measured samples, because it is not possible to manipulate the environment in a controllable manner. In view of this, novel approaches are necessary to unravel the complex interactions of environmental, genetic and developmental events. One of the most promising strategies is the development of animal models of human behavioural disorders. In the past, this approach has focussed on hypothesis-driven analysis either of pharmacological models (e.g. PCP, amphetamines) or the generation of lesions in specific Correspondence: Dr MJH Kas, Department of Pharmacology and Anatomy, Behavioural Genomics Section, Rudolf Magnus Institute for Neuroscience, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht 3584 CG, The Netherlands. E-mail: [email protected] Received 14 September 2006; accepted 29 September 2006; published online 21 November 2006 brain areas; genetic analysis has tended to focus on the analysis of specific knockout mice based on candidate gene approaches, either using human susceptibility genes or genes which modulate candidate neurotransmitter systems such as dopamine.1 Here, a behavioural domain concept will be introduced that focuses on the genetics of naturally occurring behavioural domains (such as social interaction, appetitive motivation, memory function) that are each relevant in varying degrees to animal behaviour and human neuropsychiatric disorders. This approach is timely as domains of disease-related traits will become increasingly important in clinical medicine as traditional diagnostic boundaries between disorders are eroded. We believe that interspecies trait genetics rather than complex syndrome genetics will optimize genotype–phenotype relationships for neuropsychiatric disorders and generate powerful new disease models that will facilitate the identification of biological substrates, their developmental consequences, and the environmental modulators underlying these disorders. However, there is still considerable scepticism on the validity of animal models of human behaviour. To further consider their validity, we propose that, in order to identify shared genotype–phenotype relationships in animal and humans, the same gene should affect analogous phenotypes in both species. Thus, the approach depends on conserved gene function, the presence of functional polymorphism in that gene in both species, and thirdly on the choice of an appropriate analogous phenotype in both the model species and in humans. The choice of phenotype in the model organisms is critical. Genetics of behavioural domains MJH Kas et al The current diagnostic scheme Current nosology for the diagnosis of psychiatric disorders (e.g. DSM-IV and ICD10) separates each into non-overlapping diagnostic categories, based not on their underlying aetiology but on the symptoms of the disease, that is, the patient’s behaviours and selfdescribed mental state. While these diagnostic categories are reliable, in that they form the basis for clinical management, communication and treatment of psychiatric disorders, they are not necessarily valid in terms of reflecting the underlying neurobiology of the disease. The main difficulty in the construction of biologically valid diagnoses is the lack of biomarkers; unlike other complex disorders such as diabetes or blood pressure, there are no well-established physiological, biochemical or other tests, which can be used to define the parameters of the illness. The uncertain relationship between diagnosis and underlying aetiology has created difficulties for aetiological research and made the generation of appropriate disease models very difficult. Despite this, psychiatric disorders consistently show high heritability and there have been a few notable successes in the identification of genetic and environmental risk factors. As aetiological research into psychiatric disorders progresses, there has been a recent rethinking of these diagnostic boundaries and their usefulness in treatment and classification. This is based on the notion that there is more aetiological overlap between psychiatric disorders than previously thought, and that they might better be described as domains of disorder-related traits rather than separable categories (Figure 1). Indeed diagnostic boundaries between psychiatric disorders are often unstable and lack specificity.2 An example of this is the distinction between the eating disorders anorexia nervosa and bulimia nervosa; they clearly have partially shared aetiology, and the former often resolves into the latter over time.3,4 Likewise, while the psychoses, schizophrenia and bipolar disorder have been historically classified into non-overlapping categories with distinct aetiologies (the Kraepelinian dichotomy), this separation is at least partially artificial. Figure 1 Schematic showing overlap between bipolar disorder, schizophrenia and depression. BPD stands for bipolar disorder. The alternative view, that psychiatric disorders are not separate entities but continuum, is supported by gradually accumulating evidence from epidemiology and genetics. For the major psychoses, both linkage5,6 and association studies support shared aetiology, with genes such as neuregulin 1, dysbindin, DISC1, G72/G30 and brain-derived neurotrophic factor, appearing to be risk factors for both diagnostic categories.7–10 Perhaps the most promiscuous example is brain-derived neurotrophic factor, BDNF. Polymorphisms in this gene have been associated with schizophrenia, bipolar disorder, major depression, anorexia nervosa and bulimia nervosa.11–15 So if these aetiological risk factors do not map specifically to the classical diagnostic categories in psychiatry, what is the route from gene to psychiatric illness? One approach to revealing this is the use of symptoms and clinical subtyping to understand the role of each gene in causing psychiatric disorders. For example in the major psychoses and depression, factor analysis suggests a set of five domains: reality distortion, disorganization, psychomotor poverty, mania and depression.16 Analysis of whether individual genetic risk factors have a specific effect on symptom domains is an important and relatively new approach which has great promise for tackling the management of symptom heterogeneity in patients. However, since symptoms and clinical subtyping are simply refinements of psychiatric diagnoses they are not necessarily closer to the underlying disease aetiology than the clinical diagnosis itself, and thus may not help to solve the underlying problem of the validity of psychiatric diagnoses or the development of disease models. In order to do this it is necessary to move further down the chain from clinical diagnosis towards underlying aetiology. 325 The endophenotype, intermediate phenotype or biomarker Recently, Gottesman and Gould17 put forward the psychiatric endophenotype concept to facilitate the identification of genes relevant for neuropsychiatric disorders. Endophenotypes, which are expected to have lower genetic heterogeneity than clinical diagnoses, may represent simpler clues to genetic underpinnings than the disease syndrome itself. Furthermore, endophenotypes may not be specific to one psychiatric disorder but have overarching effects impacting on several different diagnoses.2 This promotes the view that psychiatric diagnoses can be deconstructed to facilitate more straightforward and successful genetic analysis. In light of further understanding complex interactions between development and gene-environment for human neuropsychiatric disorders, we would like to extend this concept by introducing complementary interspecies genetics. As mice do not get schizophrenia, this requires the identification of complementary traits between animals and humans that are relevant to the behavioural spectrum, that is the mouse equivalent of a human Molecular Psychiatry Genetics of behavioural domains MJH Kas et al 326 neuropsychiatric endophenotype. While genetic validity for basic interspecies physiological processes has become available, such as in cholesterol levels18 and glomerulonephritis,19 the road to complementary genetics of complex behavioural traits still needs to be paved. Thus, while there is evidence of the conserved association of some genes, such as MAOA enzyme activity and aggressive behaviour,20,21 and leptin and feeding behaviour22 which provide a strong indication for conservation of gene function in behaviour across species, these are really single gene deficits, not complex traits. The fundamental hypothesis of complementary behavioural endophenotypes between mice and men has, thus far, been poorly addressed. Interspecies conservation of genetic variation in behaviour From an evolutionary point of view, interspecies conservation of genetic variance in behaviour should be based on its involvement in common survival mechanisms that allow adaptation to the ever-changing environment. Indeed, survival of a species in its environment relies exquisitely on proper behavioural responses to external cues. For example, behaviours such as exploration for food or social interaction have evolved to deal with variation in the availability of food resources or reproduction partners, on one hand, and with the presence of threat from natural predators or territorial attacks from con-specifics, on the other hand. Therefore, we propose that the identification of biological substrates underlying basic behavioural survival mechanisms will greatly contribute to our understanding of normal and maladaptive behaviour in animals and humans, however, novel research approaches are necessary to tackle its complexity. Behavioural phenotyping in rodents: the leap from mouse to man Rodents, like other mammals, are fairly precise physiological and biochemical models of humans, with near identical biological pathways for the regulation of many basic processes such as feeding (leptin, ghrelin etc.), plasma lipid function, blood pressure et cetera, which are fine-tuned to the individual species environment and are subject to the parallel effects of genetic variation across species. Despite this many observers are sceptical about the use of animal models of complex human diseases, especially in psychiatric disorders where many of the behaviours which form the core of diagnostic systems (such as paranoid ideation, auditory hallucinations, drive for thinness and undue concern over weight and shape) do not exist in a readily accessible form in the rodent. However, many disease behaviours, especially their endophenotypes, exist in both species at a more basic behavioural level, such as within domains related to anxiety, activity, cognition and social interaction. Many specific elements related to these Molecular Psychiatry domains, such as impulsivity, set-shifting, memory function and anticipatory motivation are conserved across many species; for example it is evident that setshifting is conserved in humans, primates and mice, and that similar tests can be used across all species.23 Traditionally, behavioural phenotyping in rodents has been mainly addressed by means of hypothesisbased animal models (such as dopamine dysfunction) and behavioural tests that assess various interacting domains. Often used behavioural tests in basic neuroscience, such as the open field, elevated plus maze and Morris water maze tests, consist of brief assessments of animal’s fear, cognitive and motor activity levels when exposed to a novel environment. These tests are highly sensitive to environmental factors,24 such as human interference25 and the animals own environment (e.g. enriched versus basic caging26) and are also heavily dependent on the motor activity levels expressed by the animal under the test condition.27 In that respect, we recently proposed the introduction of longitudinal monitoring in home cage environments that can be designed to genetically dissociate behavioural components fundamental to survival.27 Translation of these behavioural components from mouse to man will not always result in an obvious 1:1 mouse-to-human relationship. For example, translational research with respect to the expression of motor activity levels and of feeding behaviour are relatively easy to imagine and genetic conservation of systems regulating these behaviours is likely homologous between mouse and men, and the biological pathways involved are highly conserved.28 Cognitive function is a particular area of interest for behavioural endophenotyping, since core features such as working or episodic memory can be examined across many species,29 and cognitive dysfunction is a central feature of many neuropsychiatric illnesses such as schizophrenia.17 Attentional set-shifting is another example; an attentional set-shifting task which is formally the same in mice, rats, humans and primates is dependent on the medial prefrontal cortex in rodents and the lateral prefrontal cortex in primates, indicating that these brain areas share the same function.30 Other relationships between human and rodent behavioural components, however, are likely to be very relevant but may be less straightforward to measure. There may, for instance, be a relationship between the anticipation to a conditioned sucrose reward solution in rodents and anhedonia in depression,31 since they both reflect excitement regarding upcoming events. But traits such as central coherence, locus of control and perfectionism are conceptually more difficult to model. Taken together, we propose that genetic determinants for essential behavioural components are conserved across related species and that genetic variation in these causative genes will be observed across current psychiatric diagnosis that share behavioural domains (Figure 2). An example of an endophenotype for human behavioural disorders Genetics of behavioural domains MJH Kas et al Figure 2 The behavioural domain concept across psychiatric diagnosis. The relationship of behavioural domains to susceptibility genes will be more direct than the relationship with clinical diagnosis, since the disease will be a more heterogeneous composite of behavioural traits, which are modulated by protective and adverse life events. The contribution of these life events can also be modelled in mouse where environment can be controlled and manipulated. Note that this schematic diagram is intended to be illustrative of a behavioural domain concept, rather than demonstrate associations, which are proven by genetic epidemiology. As indicated in Table 1, behavioural domains can be deconstructed in endophenotypes that can be measured in both rodents and humans. and how this may be translated in rodents is shown in Table 1. Genetic mapping approaches Recent developments in the field of mouse genetics offer opportunities for the efficient identification of genotype–endophenotype relationships with respect to complementary behavioural domains. In the traditional concept of an animal model of human disease, one hopes to find an animal (possibly under a defined set of conditions or experimental manipulation), which mimics all aspects of a human disease. This concept makes sense in some cases, in particular for diseases that are essentially single-locus traits. An example is Huntington’s disease, in which the Huntingtin knock-in mouse exhibits a genetically precise reproduction of the human condition.32 For genetically complex disorders, however, it makes more sense to dissect the behavioural domain. For example, clinical depression is clearly heterogeneous and the genetic component includes effects from an unknown number of genes. It is much more feasible and useful to study an animal that models some portion of the disease, that may correspond to the contribution of one or some of the loci involved. No single gene knockout or selection line is likely to represent the full genotypic and phenotypic complexity of the disease. This distinction also reflects the difference between the study of models of singlelocus traits, where the gene is known, and a mechanism is to be elucidated and complex traits, where the challenge is gene identification. There is an increasing appreciation of the properties of the set of mouse inbred strains which have been established over the last century of mouse genetics. Data accumulated on each of this diverse collection of over 500 strains allows strains to be chosen that cover a range of phenotypic variation in whatever domain is of interest (http://aretha.jax. org/pub-cgi/phenome/mpdcgi?rtn = docs/home). Traditionally, such strain combinations would be used to set up a cross or segregating population for genetic mapping purposes. The limitation here is that each of the progeny is unique and not only does this create an expensive genotyping requirement, it places severe limits on the detail and statistical power of phenotypic characterization. One approach that deals with such heterogeneity is to use haplotype sharing approaches to analyse panels of inbred strains directly for QTL mapping.33 This approach is limited by the characteristics of the inbred strain panel whose makeup owes much to historical chance. Genetic Reference Populations (GRPs)34 with more optimal genetic properties are available or under construction. The prototype is the Recombinant Inbred (RI) panel which is generated from a cross between two inbred strains followed by an F1 intercross and 20 generations of inbreeding.35 The best characterized mouse RI panel, BXD, has been a workhorse of behaviour genetics since the early 1990s.36 The RI approach has been used very effectively for QTLs in plant breeding, where selfing and large progenies make the establishment of large panels practical. The BXD panel, of (until recently) 35 lines, gives only a coarse genetic resolution. However, several aspects of this picture have recently changed. One is the idea of treating transcript abundance37 and protein abundance or modification38 as phenotypes in their own right. This kind of genetical-genomics is an extremely promising way of examining networks of function. Although it is possible with conventional genetic crosses or outbred populations,39 using (effectively immortal) inbred GRPs allows much more value to be extracted from each (expensive) data set. This is also true of other phenotypic data, and there is a renewed interest in the importance of accumulating data from many investigators. It is now possible to not only genetically map QTLs on the BXD RI panel (recently expanded to 80 lines34), but also to correlate new data with a large database of phenotypic data including gene expression data on several tissues. This is a major aid to positional cloning projects and multivariate analysis approaches currently being explored offer a way to assign some idea of function to many of the genes whose function is currently unknown. Other genetic reference populations have been developed. Chromosome substitution (consomic) panels have been generated for two strain combina- 327 Molecular Psychiatry Genetics of behavioural domains MJH Kas et al 328 Table 1 Examples of how endophenotypes present across psychiatric disorders may be modelled in rodents and measured in humans. WCST stands for the Wisconsin Card Sorting Test Domain Endophenotype Rodents Human Psychiatric diagnosis Cognitive function Attentional set shifting/perceptual rigidity Food burying, multidimensional visual stimuli WCST, CatBat task, Haptic Illusion task; intra-extra dimensional set-shifting Eating disorders, schizophrenia Episodic or ‘episodic-like’ memory Delayed matching to place; three trial object exploration task Weschler memory scale, Rey verbal learning tests Schizophrenia Working memory Morris water maze, radial arm maze N-back, reverse digit span Schizophrenia Attention/ (impulsivity) 5-choice serial reaction time task, delayed-reinforcement paradigms Barrett impulsivity scale, sensation-seeking scales, Go/No-Go task; delay discounting task; Stroop colour word test Eating disorders, ADHD Sustained attention 5-choice serial reaction time task Continuous performance test; rapid visual information processing Schizophrenia, ADHD Activity Baseline physical activity Home cage monitoring Acti-watches, observation, questionnaire measures ADHD, anorexia nervosa Appetitive motivation Food anticipation activity Starvation-induced hyperactivity Behavioral approach (BAS) and behavioral inhibition (BIS) scales, Motivational Trait Questionnaire, Chapman Social and Physical Anhedonia Questionnaire Depression, eating disorders Social interaction Social recognition/ social discrimination Resident mice versus social intruder Social responsiveness/ communication, theory of mind, facial recognition Autism, schizophrenia tions.40–42 This is done by repeated backcrossing to produce strains each with a single chromosome of one strain on the background of another. This is attractively simple to analyse and offers the simplification of multilocus traits with only a single chromosome segregating. This simplification is also offered by Recombinant Congenic (RC) strains, but this requires a larger panel. Each of these binary GRPs is limited by the genetic variation it encompasses (two progenitor strains), size and thus genetic resolution. Together with the increasing detail of genomic data available these form a very good armoury for the conquest of QTLs with additive effects of reasonable size. QTLs of small effect size, and those that interact are also of great interest and are likely to be more common, but to have the power to unravel these we will need a new generation of GRPs. To this end, a collaborative cross has been proposed43 and is currently under development. This has eight progenitor strains covering the full range of diversity of mouse inbred strains, and the target is to produce a thousand independent inbred lines. Molecular Psychiatry Gene environment interaction The interaction between genes and environment (G E) has long been known to influence behavioural traits and may be at the core of the development of certain personality traits and psychiatric disorders.44 G E, expressed as genetic variation in the susceptibility towards specific environmental factors, can account for the significant individual differences in vulnerability to various psychiatric disorders.45 A series of recent human epidemiological studies revealed that the development of psychiatric disorders, such as antisocial behaviour or depression can result from genotypes that mediate children’s sensitivity to environmental insults which occurred before the onset of illness.46,47 While human studies elegantly indicated the relationship between gene-environment and developmental stages, further understanding regarding the mechanisms underlying these complex interactions will be challenging when purely based on human studies. In that respect, studies using animal models of disease could contribute substantially to unravelling the causative processes.48 Genetics of behavioural domains MJH Kas et al G E is clearly difficult to study in man as environmental factors cannot be controlled and it is a considerable challenge to even collect measures of environmental factors and risks.49 Animal models offer unique opportunities to study the effects of genes, environments and their interactions on complex behaviour and physiology. Genes and environments can be manipulated or controlled in animals such that the contributions or interactions between genes and environment can be assessed. Moreover, the downstream effects (e.g. gene expression) and underlying molecular mechanisms of G E can be closely studied in animal models as they relate to specific behaviours, furthering our understanding of the susceptibility to psychiatric illnesses. Thus, although it is clear that animal models provide an ideal method for G E research, to date there has been little work done in this area. Several studies have focused on the role of environment in measuring animal behaviour, stressing the need to standardize and/or minimize environmental variation to increase the reliability and robustness of measures of behaviour.50 There is also a wealth of research on the effects of direct manipulation of the environment on animal behaviour, but the majority of these studies have focused on only one gene using mice with a targeted deletion or overexpression of the gene.51 There are a few interesting studies that parallel the work of Caspi et al.46,47 using serotonin transporter knockout mice52 and stress-reared rhesus macaques.53 Other studies have explored the effects of environmental manipulation on behaviour and physiology but have not assessed the genetic basis for individual differences in susceptibility (or resilience) in response to the environmental perturbation. Recent work has used a global approach, evaluating changes in gene expression in response to environmental perturbations within a single population of mice54 but few studies have attempted to combine environmental manipulation with genetic approaches using both behavioural and genomic read-outs.55 Given the growing evidence for the importance of G E in psychiatric disorders, there is a clear need for robust and genetically informative animal models of environment in the study of G E so that specific hypothesis regarding G E can be tested and in order to understand the mechanisms by which genes and environment interact. References 1 Chen J, Lipska BK, Weinberger DR. Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models. Biol Psychiatry 2006; 59: 1180–1188. 2 Weiser M, van Os J, Davidson M. Time for a shift in focus in schizophrenia: from narrow phenotypes to broad endophenotypes. 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