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Molecular Psychiatry (2007) 12, 324–330
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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
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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.
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