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World Psychiatry. 2004 June; 3(2): 73–83. | PMCID: PMC1414673 |
Gene-environment interactions in mental disorders Ming T Tsuang,1,2,3,4 Jessica L Bar,1 William S Stone,1,2 and Stephen V Faraone2,4 1Harvard Medical School Department of Psychiatry, Massachusetts Mental Health Center (MMHC), 25 Shattuck St., Boston, MA 02115, USA 2Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA 3Department of Epidemiology, Harvard School of Public Health, Boston, MA, U 4Psychiatry Service, Massachusetts General Hospital, Boston, MA, USA Research clearly shows that both nature and nurture play important roles
in the genesis of psychopathology. In this paper, we focus on 'gene-environment
interaction' in mental disorders, using genetic control of sensitivity to
the environment as our definition of that term. We begin with an examination
of methodological issues involving gene-environment interactions, with examples
concerning psychiatric and neurological conditions. Then we review the interactions
in psychiatric disorders using twin, adoption and association designs. Finally, we
consider gene-environment interactions in selected neurodevelopmental disorders
(autism and schizophrenia). Keywords: Genetic factors, environment, interaction, neurodevelopmental disorders Family, twin, and adoption studies have firmly established the roles of
both genes and environment in mental disorders. It remains difficult, however,
to find genes for these disorders, and to characterize the particular environmental
circumstances under which psychopathology emerges. The reason for this difficulty
lies in the complex nature of mental disorders. Many disorders – like
many normal physiological conditions (e.g., blood pressure) and cognitive
abilities (e.g., intelligence) – probably result from the combined action of
multiple genes of small effect together with a variety of environmental factors.
In addition, genetic and environmental factors interact with each other in
complex ways to influence phenotype ( 1).
In other words, individual genes and environmental factors exert their effects
only via interaction with other genes and other environmental factors. The
issue is no longer one of nature versus nurture; rather,
we must ask: how do genes and environment interact to produce
a behavioral phenotype? In this paper, we will focus on 'gene-environment interaction' in mental
disorders, using genetic control of sensitivity to the environment as our
definition of that term ( 2). Gene-environment
interaction occurs when environmental influences on a trait differ according
to a person's genetic predispositions, or when a person's genetic predispositions
are expressed differently in different environments. Interaction phenomena
are important. By ignoring interactions, true genetic and environmental effects
can be obscured, which leads to false negative results and, more generally,
to inconsistent findings in the literature. The subsequent discussion begins with a consideration of methodological
and measurement issues involving gene-environment interactions, with examples
concerning psychiatric and neurological conditions. This will be followed
by a representative review of interactions in psychiatric disorders using
twin, adoption and association designs. Finally, gene-environment interactions
will be considered in selected neurodevelopmental disorders (autism and schizophrenia)
to highlight their potential to shed light on underlying etiologic mechanisms
in this class of psychiatric conditions. METHODOLOGY AND MEASUREMENT ISSUES Several excellent reviews discuss some of the methodological issues and
problems involved in assessing gene-environment interaction, and the reader
is referred to these for a more detailed discussion ( 3- 7). Some of these
problems are ones of definition and assessment, i.e., in order to test for
gene-environment interaction, individuals must be classified according to
presence or absence of genetic and environmental risk, and the specification
of both can be difficult. Environmental exposures are difficult to define
and measure precisely, and are understudied in the context of genetic research
designs ( 8). Moreover, putative environmental
risk factors may not be truly environmental. This phenomenon is known as gene-environment
correlation, in which an individual's genotype influences his exposure to
the environment. In other words, 'environmental' factors are themselves attributable
to genetic influences. Gene-environment interaction is difficult to measure
in the presence of gene-environment correlation ( 4). On the other hand, there are several different ways of measuring genotype
( 3). Unfortunately, because of the lack
of well-established candidate genes for mental disorders (and relatively little
knowledge of the biological processes that give rise to mental disorders),
researchers have to rely on less direct ways of classifying a person according
to genetic risk. This point underscores the importance and potential impact
of the developments in molecular genetics, which will make it easier to identify
genes and genetic markers associated with mental disorders. These ongoing
advances will eventually allow the assessment of specific genotypes in specific environments,
which will facilitate direct and systematic investigations of gene-environment
interactions. The impact of advances in molecular genetics (i.e., identifying genetic
variants associated with mental disorders) can be illustrated using the case
of Alzheimer's disease (AD). An allelic association exists between AD and
the ε4 allele of the apolipoprotein E (APOE) gene ( 9), which results in a 6-fold risk for AD in individuals with
one or two copies of this allele ( 10).
APOE is considered a 'susceptibility gene', because it is neither necessary
nor sufficient for the development of AD. Other genes or environmental agents
must be present for the ε4 allele to increase risk for AD.
One of the earliest environmental risk factors associated with AD was a history
of head injury ( 11, 12). Because a positive family history was also a risk factor
for the disease ( 13), attempts were
made to find evidence for gene-environment interaction, using family history
as an indicator of genetic risk. However, results of early studies failed
to demonstrate convincing evidence of interaction ( 14, 15). Mayeux et al ( 16) then studied the combined effects of head injury and
genetic susceptibility on risk for AD, and found no increase in risk associated
with head injury in the absence of the ε4 allele, a two-fold
increase in risk with ε4 alone, and a 10-fold increase in
risk with both ε4 and a history of head injury. These findings
and those from subsequent studies examining frequency of the APOE-ε4
allele in patients with head injury have led to hypotheses regarding a biological
mechanism whereby head injury contributes to the pathogenesis of AD by increasing
beta-amyloid precursor protein (APP) deposition in the cerebral cortex, which
exacerbates the effect of the APOE-ε4 allele (which is thought
to be related to cerebral beta-APP deposition). Malaspina et al ( 17) found similar
evidence for gene-environment interaction in schizophrenia, another mental
disorder that has been associated with head injury. Using membership in multiplex
schizophrenia and bipolar pedigrees as proxies for, respectively, greater
and lesser genetic loading, they found that schizophrenic subjects from schizophrenic
pedigrees were more likely to have experienced a traumatic brain injury (19.6%)
than schizophrenic subjects from bipolar pedigrees (4.5%). Within the schizophrenia
pedigrees, head injury was associated with a greater risk of schizophrenia
(OR = 2.06), consistent with a synergistic effect between genes and environment.
While these results are provocative, their implications are limited by the
lack of information about schizophrenia susceptibility genes. As was the case
with AD, once these have been identified with the aid of advances in molecular
genetics, it will be relatively easy to incorporate this information into
epidemiological studies, resulting in a rapid increase in knowledge about
disease pathogenesis. Currently, alcohol use provides a paradigm for studying gene-environment
interaction similar to AD. Two polymorphisms – in the aldehyde dehydrogenase
(ALDH) and alcohol dehydrogenase (ADH) genes – are associated with risk
for alcohol dependence in Asian populations ( 18, 19), providing the basis for studies examining
the relationship between these genetic risk factors and the effects of known
environmental risk/protective factors for alcohol abuse and dependence, such
as early family rearing environment. Until now, however, most knowledge about gene-environment interaction has
come from traditional quantitative genetic studies, in which family history
and monozygotic/dizygotic (MZ/DZ) concordance are used as indices of genetic
risk. While there are methodological limitations to these studies (e.g., the
possibility of genetic misclassification), twin and adoption studies have
been influential in demonstrating gene-environment interaction effects ( 3). Twins can be a useful tool in the investigation of gene-environment interaction
( 20). For example, MZ discordant twins
can provide evidence for the influence of non-inherited characteristics on
a disorder. A greater incidence of obstetric complications (OCs) ( 21) and of dysmorphological handprint signs suggestive of
abnormal fetal development ( 22) has
been observed in MZ twins with schizophrenia than in their unaffected cotwins.
A different approach involves comparing heritabilities (i.e., the proportion
of phenotypic variance due to genetic variance) according to the presence
or absence of identified specific environmental risk factors. In addition
to having main effects on rates and/or symptom levels of a disorder, environmental
variables may also have moderating effects on the relative magnitude of genetic
and environmental influences on the disorder. This is a form of gene-environment
interaction: changes in the environment may render genes or environment more
or less salient as influences on the behavior. In other words, the amount
of variability in a disorder that is due to genetic or environmental influences
may differ at different levels of an environmental variable, distinct from
any main effect of that variable (i.e., in the absence of phenotypic change). Several twin studies have examined the impact of broad personal variables
on symptoms of mental disorders. Among these, the effects of socioregional
variables on adolescent alcohol use were examined in a population-based sample
of Finnish twins ( 23, 24). In the first study, Rose et al ( 24) found that although drinking frequencies were similar
for adolescents in urban and rural environments, genetic factors played a
larger role in urban areas, whereas shared environment had a greater influence
in rural settings. In an effort to better understand the nature of this urban/rural
effect, this same group then examined more specific, continuous measures of
the environment, and found that the magnitude of genetic influences on drinking
frequency was nearly five times greater in environments characterized by a
greater percentage of young adults, higher migration rates, and proportionately
greater alcohol sales ( 23). Marital status has been found to exert moderating effects on the expression
of genetic and environmental influences on alcohol consumption ( 25) and on symptoms of depression ( 26) in a sample of female adult Australian twin pairs. Genetic
influences accounted for a greater proportion of the variance in both alcohol
consumption and symptoms of depression in unmarried twins than in twins involved
in a marriage-like relationship. In other words, having a marriage-like relationship
reduced the impact of genetic influences on psychiatric symptoms. Religiosity
has also been found to have a moderating effect on alcohol use initiation
( 27) and disinhibition, as measured
by the Sensation Seeking Scale ( 28)
in a Dutch twin sample. In both of these studies, while there was no association
between religious upbringing and either alcohol use initiation or disinhibition,
the influence of genetic factors on these variables was much greater in subjects
without a religious background. These results suggest that receiving a religious
upbringing, like being involved in a marriage-like relationship, may act as
a protective factor in reducing the influence of genetic liability to psychiatric
symptoms ( 26). These studies are consistent with a sociological perspective that regards
heritability as representing an individual's proportion of actualized genetic
potential ( 29). According to this definition,
the reason that heritability varies across environmental contexts is because
different environments provide different opportunities for genetic potentials
to be actualized. Structured situations are those that provide relatively
unambiguous cues to guide behavior. Conversely, less structured situations
are more ambiguous ( 30, 31). Because there are few salient cues in the environment,
individuals must rely to a greater extent on their own disposition to guide
behavior. It follows that the causes of behavior in structured situations
should be more situational than dispositional, whereas individual differences
are more likely to be the causes of behavior in less structured situations.
Consistent with this prediction, in the above studies, heritabilities for
various clinical problems increased in environments that were less controlling,
i.e., in subjects living in urban areas, in subjects who were unmarried, and
in subjects without a religious upbringing, and the impact of shared environmental
influences was greater in environments that theoretically provided a narrower
range of opportunities to express individual differences in behavior. Results
such as these, demonstrating differences in genetic and environmental influences
in differing environmental circumstances, provide one explanation for the
heterogeneity among heritability estimates for the same disorder, and point
to the need to incorporate measures of the environment into genetically informative
designs. Kendler and colleagues have also used large population-based twin samples
to study the impact of life events on depression and anxiety in women. Studies
investigating the comorbidity of generalized anxiety disorder (GAD) and major
depression (MD) in female twins found that all of the genes that influenced
lifetime risk for GAD and MD appeared to be completely shared between the
two disorders ( 32- 34). Common or familial environment was not a factor in the
etiology of either disorder. Some non-shared or unique environmental factors,
however, may be relatively specific to either GAD or MD (e.g., stressful life
events), while others may be both depressogenic and anxiogenic. These results
suggest that it is likely that environmental factors are largely responsible
for whether a female expresses genetic vulnerability as anxiety or depression.
Roy et al ( 35) replicated these results
in a clinical twin sample that included both male and female subjects and
suggested that MD may be associated with stressful life events that involve
loss, while GAD may be primarily related to life events that involve danger,
consistent with the fact that MD and GAD have been associated with different
sociodemographic predictors ( 36). Following these results, Kendler et al ( 37)
set out to investigate the relationship between stressful life events and
the onset of depression in this sample. They found that the risk of onset
of a major depressive episode in the month following the occurrence of any
of four types of severe life events (death of a close relative, assault, divorce
or marriage breakup, serious marital conflict) was highest in those at greatest
genetic risk (as gauged by twin concordance). The one-month probability of
onset of MD in individuals at lower genetic risk (i.e., with an unaffected
cotwin) was 0.5% and 6.2%, respectively, depending on the absence or presence
within that month of a severe life event. For individuals at high genetic
risk (i.e., with an affected cotwin), the probabilities were 1.1% and 14.6%,
respectively. These results are indicative of a gene-environment effect, in
which genetic susceptibility increases an individual's sensitivity to the
psychological impact of stressful life events. Genetic factors, however, play a role in individual exposure to life events
( 37) and, moreover, the genetic liability
to experience stressful life events overlaps with the genetic liability for
depression (i.e., gene-environment correlation) ( 38).
Thus, Silberg et al ( 39) conducted
a more rigorous test of this gene-environment interaction effect by examining
the relationship between risk for anxiety and depression and independent life
events, i.e., those life events involving no genetic mediation, in a sample
of adolescent female twins. They found a gene-environment effect similar to
that of Kendler et al ( 37), in which
the occurrence of an independent stressful life event in the past year (a
new stepbrother/stepsister, brother/sister leaving home, father losing his
job) had no effect on the depression scores of girls at low genetic risk (as
indexed by the absence of parental emotional disorder), but significantly
increased the scores of girls who had a parent with a history of depression
or anxiety. In addition, life events exerted a moderating effect on the genetic
and environmental influences on depression and anxiety, such that genetic
variance increased with increasing exposure to stressful life events, a result
in accord with the hypotheses regarding protective environments advanced in
the studies discussed above ( 23, 26). This study illustrates just one of the
difficulties in finding evidence for gene-environment interaction in complex
disorders: genes influence both exposure and susceptibility to environmental
risk factors. Gene-environment correlation and gene-environment interaction
both operate to influence phenotype, and disentangling the two will require
conceptual advances such as that illustrated by this study. More than twin and family studies, adoption studies allow for the separation
of genetic and environmental effects, because children do not share home environments
with their biological parents. The major drawback to this type of design is
that adoptive homes underrepresent high-risk environments, i.e., those at
the extremes of poverty and deprivation (see Rutter and Silberg ( 4) for additional limitations). This is especially important
because it has been suggested that gene-environment interactions may only
exist at the extremes of genetic and environmental variation, hence adoption
studies may underestimate the effects of environmental risk and protective
factors and may not always detect true gene-environment interactions ( 40). For the most part, adoption study investigations of gene-environment interaction
have used biological family history of mental disorder as an indicator of
genetic risk, and examined its relationship to psychosocial risk and protective
factors in the adoptive family. Results from studies investigating the effects
of family variables such as family conflict, poor cohesion, and deviant communication
indicate that a wide range of mental disorders, including alcoholism, antisocial
behavior (ASB), depression, and schizophrenia share these risk factors and
that, for each disorder, these environmental influences interact with genetic
risk to exacerbate psychiatric symptoms. An early adoption study found that male (but not female) adoptees with
an alcoholic biological parent were more likely to develop certain types of
alcoholism if they were also at environmental risk, based on adoptive family
characteristics, pre-placement conditions, and age at adoptive placement ( 41). Cutrona et al ( 42) found evidence for gene-environment interaction in alcoholism
in a US sample of adoptees. Neither a biological background of alcoholism
nor any family environmental variables increased risk for alcohol abuse or
dependence in female adoptees. However, women (but not men) with at least
one alcoholic biological parent who also experienced early-life family conflict
and/or adoptive family psychopathology were more likely to become alcoholic
than those with low levels of family conflict. In other words, neither a biological background
of alcoholism nor environmental stress alone was sufficient to lead to alcoholism
in the adoptees, but a combination of the two increased the risk. Adoption studies have also found evidence for a gene-environment effect
on ASB, such that individuals at high genetic risk are more sensitive to adoptive
family conflict. Cloninger et al ( 43)
found a synergistic effect for genetic and environmental risk factors in a
Swedish sample, such that adoptees at both genetic risk (i.e., criminal biological
parents) and environmental risk (i.e., adverse rearing experiences and poor
quality adoptive placements) had significantly higher rates of petty criminality
than adoptees at either biological or environmental risk alone. In other words,
adoptees with genetic predispositions towards criminality also were more likely
to be affected by negative environmental experiences. Rutter ( 44) noted that a problem with this type of study involved
the use of parental criminality as a measure of genetic risk, both because
it was crude, and also because it did not provide information on the mechanism
of the genetic effect. Parental criminality could be an index of any of a
number of psychopathological, physiological, or cognitive risk factors in
the child. Cadoret and colleagues conducted a series of adoption studies investigating
ASB and consistently found evidence for an interaction between a genetic background
of ASB and an adverse adoptive home environment ( 45- 48). In the most recent study, antisocial
personality disorder (ASPD) and substance abuse/dependence in the biological
parent were used as indicators of genetic risk, and environmental risk was
indexed by a composite measure of marital, legal, and psychological problems
in the adoptive parents ( 48). These
family environmental factors increased the risk for childhood aggression,
adolescent aggression, and conduct disorder (but not adult ASB), but only
in the presence of a biological background of ASPD. There was virtually no
effect of the environment on those adoptees not at genetic risk. Unlike the
earlier studies which combined ASB and substance abuse as an index of genetic
risk ( 46), this study was able to separate
the genetic influences associated with both. The results showed that a biological
background of alcohol abuse did not interact with adverse adoptive home environment
to increase risk for ASB, which demonstrates the specificity of the genetic
diathesis for ASB. Not all adoption studies, however, replicated the observed gene-environment
interaction between a biological background of antisocial behavior/traits
and environmental risk, in the form of adoptive parent antisocial behavior/traits
( 49, 50).
Moreover, evidence for gene-environment correlation in adoptee ASB demonstrates
that additional factors may be operating to influence child ASB, and that
care must be taken when conducting studies investigating gene-environment
interaction. Both Ge et al ( 51) and
O'Connor et al ( 52) found an association
between a biological background of antisociality and adoptive parenting behavior
that was mediated by the child's behavior, such that adoptee antisociality
led to harsh and inconsistent behaviors on the part of the adoptive parents,
which increased the child's own antisocial behaviors. The same disturbed adoptive parent variable examined in Cadoret et al ( 48) also interacts with genetic risk factors
to influence MD in women. In another study, for instance, Cadoret et al ( 53) showed that females (but not males) with
a genetic background of alcoholism are at increased risk for MD if they live
in an adoptive family with a high number of disturbed behaviors. There was
no effect of environmental stress in the absence of an alcoholic background.
This finding is in accord with theories suggesting that alcoholism is a marker
for genetic risk that leads to depression and alcoholism in females, but only
alcoholism in males ( 54). An adverse adoptive home environment has also been implicated as a source
of potential risk for schizophrenia. Findings from the Finnish adoption studies
show an increased risk for schizophrenia in the biological offspring of schizophrenic
versus non-schizophrenic parents, but only for those high-risk adoptees who
were also exposed to a dysfunctional family rearing environment ( 55, 56). Wahlberg
et al ( 57), also using the Finnish
sample, demonstrated that symptoms of thought disorder (i.e., an indicator
of schizophrenia vulnerability) in offspring of schizophrenic mothers were
more probable when they were raised by adoptive mothers who themselves showed
elevated levels of 'communication deviance'. In contrast, offspring of schizophrenic
mothers, raised by adoptive parents with low communication deviance, were
less likely to show thought disorder. There was no relationship between thought
disorder in control adoptees and communication deviance in the adoptive parents. In
other words, this gene-environment interaction effect suggests that adoptees
without a pre-existing genetic liability were not vulnerable to the effects
of a disturbed family environment (at least with respect to thought disorder),
and individuals with a pre-existing genetic liability expressed this liability
only in the presence of additional adverse environmental factors. Rutter and Silberg ( 4) suggested
that results such as these from twin and adoption genetic studies, i.e., demonstrating
gene-environment interaction, have so far been supportive of the hypothesis
that the impact of environmental risk factors on psychopathology is slight
in the absence of genetic risk. It is likely that research into gene-environment
interaction will progress once genetic marker information can be incorporated
into quantitative genetic studies, so that subjects with known genotypes can
be exposed to environmental manipulations, allowing for a more experimental approach
to the investigation of nature-nurture interplay in human beings. One method
of incorporating genotypes into studies of gene-environment interaction is
considered in the following section. Association studies provide a potentially useful approach to the detection
of gene-environment interactions in mental disorders (i.e., controlling and
manipulating both genes and environment). They do provide clues about the
interaction in various (non-human) animal protocols ( 58, 59). The risk
and protective effects of perinatal rearing experiences (e.g., maternal separation
or loss, abuse or neglect, social deprivation) on anxiety- and depression-like
behaviors have been demonstrated in both rodents and nonhuman primates ( 60, 61).
For example, genetically different strains of rodents that vary in their response
to stress show additional differences in gene expression and in behavior when
exposed to adverse rearing experiences. Gene-environment interaction effects might thus provide one explanation
for inconsistent findings among association studies between genetic markers
and mental disorders, just as they may explain the variability in heritability
estimates for the same disorder. For example, the role of the serotonin transporter
gene (5-HTT) in anxiety in humans is controversial. While some studies have
reported an association between a functional polymorphism in the regulatory
region of this gene (5-HTTLPR) and anxiety-related behavior ( 62, 63), others did
not replicate the finding ( 64). Similar
contradictory findings have been reported between this polymorphism and both
MD and bipolar disorder ( 64). Studies
in rhesus monkeys, however, have demonstrated the role of gene-environment
interaction in the association between this polymorphism and anxiety-related
behavior ( 65, 66). Monkeys at greater genetic risk (i.e., with a greater
number of the high-risk, low-activity allele) show differences in measures
of 5-HTT expression that are associated with various adverse behavioral outcomes
(e.g., lower rank within a social group, less competent social behavior, and
greater impulsive aggression), as well as greater anxiety- and depression-related
behavior (e.g., diminished orientation, lower attentional capabilities, and
increased affective responding). These genotype effects are more pronounced for
peer-raised (i.e., separated at birth from mothers) than for mother-raised
monkeys. Another gene whose association with human behavior is controversial is
the dopamine D2 receptor gene (DRD2). Associations have been reported between
DRD2 variants and several psychological disorders and traits, including alcoholism
and other substance use disorders, schizophrenia, post-traumatic stress disorder,
and certain personality traits, although, with the exception of schizophrenia
( 67), none of these associations has
been replicated with enough consistency ( 68).
However, some recent studies using human subjects have demonstrated evidence
for association, and for gene-environment interaction, by taking account of
environmental measures. An association between the DRD2 Taq1 polymorphism on chromosome 11 and
alcoholism was first reported in 1990 ( 69).
Since that time, many attempts at replication have taken place, with variable
results ( 70). Meta-analyses of DRD2/alcoholism
studies found that, overall, alcoholics had a higher prevalence of the high-risk
allele than controls, and that the prevalence was higher in more severe alcoholism
than it was in less severe alcoholism ( 71).
Still, the association remains controversial ( 72- 74). Madrid et al ( 75) measured alcoholism
and stress exposure in a sample of Honduran males, and found that neither
was related to DRD2 genotypes. They did find, however, a significant interaction
between genotype and stress score, such that individuals homozygous for the
low-risk allele had similar alcoholism scores regardless of level of stress
exposure. Alcoholism scores for heterozygous individuals increased modestly
with increasing stress, and alcoholism scores for individuals homozygous for
the high-risk allele increased greatly with stress. These results suggest that:
a) individuals at genetic risk have a greater sensitivity to stress than those
not at genetic risk; and b) the presence of environmental stress may be necessary
for the development of alcoholism in this population. Similar relationships between DRD2 genotype and environmental stress occur
with regard to both cognitive markers and the personality trait of extraversion.
Berman and Noble ( 76) found no relationship
between family stress and cognitive markers (including visuospatial ability
and event-related potentials, both of which have been linked to alcoholism
( 77, 78))
in preadolescent boys lacking the Taq1 high-risk allele. However, in boys
with one or two copies of this allele, cognitive scores were negatively correlated
with family stress scores. There were no differences in performance scores
between boys from low-risk and high-risk family environments, regardless of
genotype. Ozkaragoz and Noble ( 79)
measured extraversion in a sample of children of alcoholic or control parents,
under the hypothesis that children growing up in an alcoholic home would experience
more environmental stress than those growing up in a non-alcoholic home. While
there were no significant main effects of DRD2 genotype or family environment
on extraversion, there was a significant gene-environment interaction such
that children with the high-risk allele displayed greater levels of extraversion
when living in an alcoholic than in a non-alcoholic home, again suggesting an
increased sensitivity to stress in those indidivuals at high genetic risk. Interestingly, among Honduran males living in a less stressful environment,
subjects at low genetic risk (i.e., with no copies of the high-risk allele)
received higher alcoholism scores than subjects at high genetic risk ( 75), and the adolescent boys at low genetic
risk received higher extraversion scores when living in a non-alcoholic family
than an alcoholic family ( 79). In other
words, results from these studies suggest that greater psychopathology is
associated with a less stressful environment in subjects who do not possess
the high-risk DRD2 Taq 1 allele. One potential explanation for this phenomenon
is that individuals with different DRD2 genotypes might respond to stressors
in different ways. For example, Ozkaragoz and Noble ( 79) suggest that boys possessing the high-risk allele might
cope with stress by increasing their level of activity, whereas boys with
the low-risk allele might cope with stress by decreasing their activity. Thus
it would be that, in a less stressful environment, boys at low genetic risk
would appear to be more active than boys at high genetic risk. GENE-ENVIRONMENT INTERACTION IN NEURODEVELOPMENTAL DISORDERS Neurodevelopmental disorders are particularly likely to express gene-environment
interactions, because development itself is a dynamic process that results
from a constant interplay between genetic and environmental determinants.
The combination of these etiologic factors begins early in development, with
a greater liability for psychopathology arising when genetic susceptibility
interacts with adverse biological consequences of untoward environmental events
in the pre- or perinatal period. This etiology may result in a variety of
outcomes based on the severity of both genetic and environmental 'loadings'
for a particular disorder, and also on the presence or absence of other genetic
and environmental 'protective factors', which may lower the risk for subsequent
psychopathology. Two examples of neurodevelopmental disorders, autism and
schizophrenia, will be reviewed for evidence of gene-environmental interactions. While twin studies provide clear evidence of a genetic basis for autism
( 80, 81),
environmental factors also play a major role, although convincing evidence
for any particular environmental factor is lacking ( 82). For example, twin studies show evidence of increased
OCs among autistic members of discordant MZ twin pairs ( 80, 83), but perinatal
adversity may be a consequence, rather than cause, of autism ( 84). The work of Pletnikov et al ( 85, 86) provides an example of how animal models
may be used to test hypotheses about gene-environment interactions. Viral
infections have been hypothesized to play a role in autistic disorders ( 87, 88),
and neonatal Borna disease virus (BDV) infection has been used as an experimental
teratogen in animal studies to induce neurodevelopmental damage and behavioral
deficits similar to those found in autistic spectrum disorders. In one study,
Pletnikov et al ( 85) exposed different
strains of rats to BDV neonatally to study potential gene-environment interactions.
Significant strain differences were evident in brain pathology, behavior,
neurochemistry (monoamine brain systems), and in the response to pharmacological
treatments. For instance, one strain displayed a significantly greater thinning
of the neocortex compared to the other, which was associated with greater
novelty-induced hyperactivity and impaired habituation of the acoustic startle
response in a prepulse inhibition paradigm. Results such as these provide support
for an interaction between specific environmental risk factors (i.e., viral
infection) and genetic liability (i.e., the strain of mouse) in the etiology
of a neurodevelopmental disorder, and suggest novel avenues for research into
other putative disorders of neurodevelopment. The importance of both genetic and environmental factors in schizophrenia
is well-established in behavioral genetic and, more recently, molecular genetic
studies ( 89). While the risk of developing
schizophrenia is associated strongly with the number of shared genes between
a family member and an individual with schizophrenia, no degree of shared
genes results in a certainty of developing the illness. For example, having
two parents or an MZ twin with schizophrenia results in a risk of approximately
50% for developing the disorder. If having the same genes were the only etiological
factor, then the risk should be close to 100% in these cases ( 1). Instead, the interaction between genetic liability and
environmental factors plays an important role in determining outcome. Environmental
factors implicated in the development of schizophrenia range from biological
to psychosocial in nature and include, among others, pregnancy and birth complications,
location of birth/residence, and family environment ( 90). Recently, we modified Paul Meehl's use of the term 'schizotaxia' ( 91) to describe the liability to schizophrenia
or schizophrenia-like conditions based on the theoretical premise that the
neurobiological basis for schizophrenia is formed by the integrated effect
of genes and adverse environmental risk factors. Our reformulation ( 92) describes genetically vulnerable individuals
who are probably exposed to early adverse events (e.g., OCs) that result in
abnormal development of certain brain structures. This liability presents
from childhood as schizotaxia, which is expressed through a combination of
cognitive, neurobiological and social skill deficits that vary in severity.
For most individuals, the condition remains stable throughout their lifespan,
but for some, a combination of the liability with later adverse environmental
events (e.g., substance abuse, or stressful psychosocial circumstances) may predispose
to the development of psychosis and chronic schizophrenia. Consistent with the view of schizotaxia as resulting from a combination
of genetic and environmental factors, several studies demonstrate evidence
for an interaction between neonatal insults and genetic susceptibility to
schizophrenia. For example, these insults likely include OCs and exposure
to viral infections (including herpes simplex) ( 93).
The times of greatest vulnerability to the developing brain may include the
2nd and 3rd trimester of pregnancy. During this period, for example, environmental
factors may disrupt neuronal migration of cells to the cortex, which results
in abnormal development of the prefrontal cortex, the entorhinal cortex, and
the hippocampus ( 94). Delivery complications associated with increased risk for schizophrenia
include fetal hypoxia, ischemia, extreme prematurity, low birth weight, and
post-term birth. Overall, pre-eclampsia is the most significant individual
obstetric risk factor for schizophrenia ( 95).
Pre-eclampsia, leading to hypoxia during pregnancy, results in fetal malnutrition
including lack of oxygen, iodine, glucose, and iron. Chronic hypoxia can result
in restricted fetal growth and subtle damage to brain regions. Moreover, blood
and oxygen deprivation due to pre-eclampsia during delivery can also result
in injury to the hippocampus and cortex ( 96).
Seidman et al ( 97), utilizing the New
England cohort of the National Collaborative Perinatal Project, demonstrated
a relationship between obstetrical complications and neuropsychological deficits
in children at 7 years of age. Low birth weight had the strongest association
with neuropsychological impairments, followed by an index of inferred hypoxic
insults, and then by maternal conditions suggesting chronic hypoxia. Zornberg et al ( 98) reported results
from a 19-year follow-up study of a large sample of individuals with a previously
documented history of birth complications, and of matched controls. The individuals
with a history of birth complications were classified according to whether
or not the complications were hypoxic-ischemia-related. A significant relationship
occurred between hypoxic-ischemia-related complications and increased risk
for schizophrenia. These data thus suggested that pregnancy and birth complications
interacted with genetic liability to increase the likelihood of subsequently developing
schizophrenia. Consistent with these findings, Cannon ( 99) reported a dose-dependent relationship between risk of
schizophrenia and severity of perinatal hypoxia in offspring of schizophrenic
parents. In contrast, birth complications were unrelated to the development
of schizophrenia in a control, low-risk group whose parents did not have schizophrenia.
Similarly, Parnas et al ( 100) followed
up offspring of mothers with severe schizophrenia and found the risk of developing
the illness was highest for those who were exposed to perinatal complications.
Pregnancy and birth complications themselves occur more frequently in schizophrenic
mothers compared to normal controls ( 93),
which raises the level of risk for their (already vulnerable) children further. Other studies also examined relationships between OCs and structural brain
abnormalities in individuals with schizophrenia and their relatives ( 95, 101).
Among these relationships, ventricular enlargement in individuals at increasing
genetic risk for schizophrenia interacted with OCs, with the association between
ventricular enlargement and OCs increasing with the degree of genetic risk.
Suddath et al ( 102) reported larger
ventricles and greater temporal lobe volumes in the affected cotwin of MZ
pairs discordant for schizophrenia. These structural differences were associated
with higher rates of OCs in the affected cotwins ( 103).
Cannon et al ( 104) reported that fetal
hypoxia was associated with reduced cortical gray matter and increased cerebrospinal
fluid among patients with schizophrenia and their non-psychotic siblings,
but not among controls. Effect sizes were greatest for low birthweight subjects,
consistent with other findings showing higher rates of subsequent schizophrenia
in individuals subjected to prenatal underdevelopment ( 105- 107). The relationship
between hypoxia and brain abnormalities was stronger among patients than siblings,
and hypoxia was related to ventricular enlargement only among patients, both
findings consistent with a gene-environment interaction model in which the
liability to schizophrenia is increased in the presence of environmental risk
factors. While hypoxia did not occur more frequently among patients than among
their unaffected siblings in this study, Rosso et al ( 108), using the same sample, found a greater number of hypoxic-associated
OCs among early-onset than among late-onset cases or siblings, as well as
an almost three-fold increased risk of early-onset schizophrenia per hypoxic
OC. Seasonality of birth is another possible environmental risk factor for
schizophrenia, with winter-spring births being associated with increased risk
( 95). The increase could be due to
a higher incidence of maternal infection (e.g., influenza), and the cumulative
evidence from many studies suggests that maternal influenza infection in pregnancy,
leading to fetal brain damage, is associated with an increased risk for schizophrenia
( 109). Support for a gene-environment
interaction effect involving winter birth comes from a study by Pulver et
al ( 110), in which winter birth was
associated with a positive family history in schizophrenic probands, although
associations in the absence of family history occur as well ( 111, 112). The nature-nurture controversy is far less germane than it once was for
understanding psychiatric disorders. Research clearly shows that both nature
and nurture play important roles in the genesis of psychopathology. As the
preceding discussion showed, gene-environment interactions are evident both
in a broad variety of mental disorders, and also in a wide range of experimental
methodologies used to assess the relative contributions of genes and environment
in mental disorders. The salience of this issue will only increase as advances in neuroscience
and molecular biology identify new potential sources of gene-environment interaction.
For example, while many studies have focused on relationships between specific
alleles and clinical diagnoses, or between independent measures of clinical
function and clinical diagnoses, there is a growing focus on 'endophenotypic'
expressions of mental disorders. Endophenotypes are features that are somewhat
intermediate between the genotype and phenotype for a particular disorder
( 113), and often involve cognitive
or neurobiological functions. Because endophenotypes may be closer to their
underlying etiologies, they open windows on the mechanisms involved in both
normal and abnormal mental functions. For example, in both patients with schizophrenia
and normal controls, Egan et al ( 114)
showed that a common polymorphism in the catechol-O-methyltransferase (COMT)
gene produced a four-fold range in COMT activity and dopamine catabolism.
The range of COMT activity in both groups was associated with a related range
of performance on a neuropsychological test of executive function, and of
the efficiency of prefrontal and cingulate cortical function during an information
processing test. Because many mental functions and mental disorders are complex,
multifactorial, polygenetic conditions ( 1, 89, 115),
results from studies like that by Egan et al clarify specific mechanisms that
likely contribute to efficient and inefficient biological function, and thus
to mental function and dysfunction. This in turn provides increasing opportunities
to specify environmental contingencies that interact with these mechanisms
to increase or decrease the liability for mental disorders. Ultimately, then, the study of gene-environment interactions will further
our understanding of how to identify, diagnose and treat mental disorders.
As the pool of potential treatment targets increases, so will opportunities
for the development of early intervention strategies for many common but difficult
to treat mental disorders ( 116- 118). While the study of gene-environment
interactions is but one of several promising ways to approach that goal, it
is one whose potential warrants additional attention. The preparation of this chapter was supported in part by the National Institute
of Mental Health grants 1R37MH4351801, R01 MH50647, R01 MH59624, R01-DA12846
and R25 MH 60485 to Dr. Tsuang, by a NARSAD Distinguished Investigator Award
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ENVIRONMENT INTERACTION IN NEURODEVELOPMENTAL DISORDERS