Genes and the social environment

5
Genes and the social environment
Jennifer H. Barnett and Peter B. Jones
Introduction
Understanding the contributions of both genes and environments is essential to
unravelling the aetiology of psychosis. In this chapter, we consider how genes
might interact with aspects of the social environment in the genesis of psychiatric
disorders. We describe evidence for such interactions from early adoption studies
to recent investigations using modern molecular genetic techniques. We discuss
the principal methodological issues of such research, and the need for clarification
of the mechanisms of gene–environment interaction. Finally we consider the
challenges that increasing knowledge of epigenetics will bring to the field.
History and overview of the field
Schizophrenia and other psychotic illnesses are undoubtedly highly heritable. For
schizophrenia, the risk of the disorder in first-degree relatives is perhaps 5%,
compared with 0.5% for the relatives of controls (Kendler and Diehl, 1993).
Concordance rates for schizophrenia are 42–50% in monozygotic (identical)
twins and 0–14% in dizygotic (fraternal) twins (Cardno and Murray, 2003);
heritability estimates for most psychotic disorders hover around 80–85%
(Cardno et al., 1999). Since concordance in monozygotic twins is not 100%,
genes cannot be ‘sufficient’ causes for psychosis, though they may be ‘necessary’,
and unaffected relatives may pass on an increased risk for disorder (Gottesman
and Bertelsen, 1989). This high heritability does not rule out the importance of
environments in the aetiology of psychosis, nor of gene–environment interactions;
in fact, gene–environment interactions contribute to the heritability estimates
produced by quantitative genetic studies (Moffitt et al., 2005).
The importance of gene–environment interactions in schizophrenia has been
clear from the very earliest quantitative genetic studies, especially those using
adoption designs (e.g., Heston, 1966; Kety et al., 1971). Adoption studies allow
Society and Psychosis, ed. Craig Morgan, Kwame McKenzie and Paul Fearon. Published by Cambridge
University Press. # Cambridge University Press 2008.

the unique separation of genetic and environmental influences, by comparing
adoptive siblings who have genetic risk (inferred from psychiatric disorder in the
biological parents) with those who do not, or by studying the effects of genetically
high-risk children raised in environmentally high-risk or low-risk adoptive fam-
ilies. There are several limitations to adoption designs, including the tendency for
adoptive families to preclude high levels of exposure to risk factors such as
deprivation and poverty (Rutter and Silberg, 2002). Nonetheless, adoption studies
have produced important illustrations of gene–environment interaction. Heston’s
classic studies demonstrated that children with biological parents with schizo-
phrenia who were adopted away were at approximately the same risk for schizo-
phrenia as those brought up by parents with schizophrenia (Heston, 1966). More
recent studies from Finland have confirmed that the environmental sources of risk
for schizophrenia have little effect in the absence of genetic risk. Tienari et al.
(2004) found that in the adopted-away children of parents with schizophrenia,
adoptive-family rearing behaviour is predictive of later schizophrenia, but has no
effect on risk for children with no familial liability. This is also the case for
individual symptoms. Wahlberg et al. (1997) showed that thought disorder was
more likely in the offspring of parents with schizophrenia adopted into families
where the mother showed communication difficulties. In contrast, there was no
increased risk for thought disorder in children with genetic risk raised in families
where the mother showed low levels of communication disturbance or in children
with no genetic risk raised in families with high communication difficulties.
A classic example of gene–environment interaction is phenylketonuria (Plomin
et al., 1997). Phenylketonuria is a single-gene recessive disorder present in about 1 in
10 000 live births, which, if untreated, leads to mental retardation. The mutation is
in the gene that produces the enzyme phenylalanine hydroxylase; individuals who
are homozygous for the mutation cannot effectively break down phenylalanine in
their food. If children with the disorder are not prevented from eating foods that
contain phenylalanine, its metabolic products build up and damage the developing
brain. Because retardation can be prevented by a relatively simple environmental

intervention (a diet low in phenylalanine), newborn babies are routinely screened
for the mutation. Phenylketonuria is, therefore, a model gene–environment inter-
action, where the phenotype of mental retardation results directly from the combi-
nation of a genetic mutation and exposure to phenylalanine in the diet.
Recently, psychiatric research has been revolutionised by molecular genetics,
such as the hunt for candidate genes for schizophrenia (Owen et al., 2004).
Although this has been slow to start, the falling cost and increasing technological
and statistical sophistication of molecular genetics makes the search for gene–
environment interactions that can be assessed at the molecular level both inevi-
table and irresistible. Perhaps because of the difficulties of determining the specific
59 Genes and the social environment
brain effects of a myriad of environmental effects (Petronis, 2004), molecular
genetic research has somewhat dominated this field. However, the search for
gene–environment interactions depends crucially on the development of similarly
sophisticated means of measuring environmental risk.
Definitions of relevant terms and concepts
Molecular genetic studies group individuals according to genotype (their genetic
constitution) or phenotype (their displayed characteristics, such as the presence or
absence of a psychotic disorder). Individuals differ in genotype owing to variation
at a particular point on a gene. Such variation could include a single nucleotide
polymorphism (SNP) (a one-letter change in the coding sequence), or a variable
number tandem repeat (VNTR) sequence, where a short segment of DNA is
repeated any number of times. If the form of the gene (or allele) on both
chromosomes is identical, the individual is said to be homozygous for that allele.
If the two copies differ, the individual is heterozygous.
Gene–environment correlation occurs where a gene influences the likelihood of
exposure to an environment. This is plausible for many putative environmental
risk factors in schizophrenia. There is evidence that genetic factors influence
exposure to obstetric complications (Marcelis et al., 1998) and to life events
(Kendler et al., 1993). Genetics also influence the likelihood of abusing alcohol,

cannabis and other illicit substances (Tsuang et al., 1996). Gene–environment
correlation can also occur where environment factors cause genetic variation.
A well known example of this is the high prevalence of sickle-cell carriers in
countries where malaria is endemic. Individuals who are heterozygous for the
sickle-cell mutation have a slight survival advantage in such countries because they
are somewhat protected against the malaria parasite (Carlson, 1999). Since homo-
zygous sickle-cell carriers have a shortened lifespan, in countries where malaria is
not an issue, the sickle-cell trait will tend to be bred out of the population.
Gene–environment correlation is likely in schizophrenia because the children of
parents with schizophrenia are the potential recipients of two correlated risks: they
may inherit genes that increase risk for schizophrenia, and they will also be
brought up in a family environment that may be affected by schizophrenia. This
process is known as passive correlation of gene and environment, where children
(passively) inherit environments that are correlated with their genetic make-up. In
contrast, evocative correlations occur where the environment is itself affected by the
child’s genotype, for example where genetic factors influence a child’s personality
in a way that elicits poor parenting behaviours. It has been suggested that the
evidence linking parenting with an increased risk for schizophrenia in the off-
spring may be interpreted in this way (Jones et al., 1994). A third type, active
60 J. H. Barnett and P. B. Jones
correlation, occurs when individuals seek out or create environments that correlate
with their genetic propensities, for example, by choosing friends with similar
talents or interests as their own.
Gene–environment correlations are described where genetics influence exposure
to environments. In contrast, gene–environment interactions occur where there is
genetic control of sensitivity to the environment (Kendler and Eaves, 1986), for
example where the effects of an environmental risk factor are moderated by genetic
predisposition. Conversely, they might also include situations where the expression
of a person’s genetic constitution is affected by the environment. Genes and environ-
ment might operate in a number of ways to cause schizophrenia: they might be

additive, where the risks for schizophrenia genes and environments simply add to
one another’s effects in determining risk for schizophrenia, or multiplicative,such
that genetic risks are multiplied by environmental exposures, or vice versa. An
alternative is a model of gene–environment synergism, where exposure to both
genetic and environmental factors would be required, to produce the disorder.
These are models of interaction at a biological, or causal, level. Statistically
speaking, however, an interaction occurs when the effect of genotype on disease
risk depends on the level of exposure to an environmental factor or vice versa.
Unfortunately, this definition depends on how risks are measured, for example, as
an odds ratio or a rate difference: the practical implication of this is that psychiatric
researchers may fall foul of claiming (statistical) interactions that would simply
not exist if their data were scaled in a different way (Clayton and McKeigue, 2001).
Unawareness of these statistical hazards might be a serious impediment to the
field. Nonetheless, it need not affect the validity of discussing the principles of
gene–environment interactions.
Recent studies of gene–environment interaction
Classical and molecular forms of genetic epidemiology have complemented one
another in contributing to the current surge in interest in gene–environment
interactions. In recent years, a number of studies have demonstrated the likelihood
of gene–environment interactions for many long-established environmental risk
factors, by studying their effects in genetically sensitive designs.
Malaspina et al. (2001) investigated rates of traumatic brain injury and mental
illness in families with at least two first-degree relatives diagnosed with schizo-
phrenia, schizoaffective disorder or bipolar disorder. They found that head injury
was associated with mental illness in families with a history of schizophrenia, but
not in those with a history of bipolar disorder. Interestingly, head injury was more
common even among the healthy relatives of patients with schizophrenia, suggest-
ing some synergism between genetic liability for schizophrenia and for head injury.
61 Genes and the social environment
Gene–environment synergism was also the subject of a recent study (van Os

et al., 2003), which investigated whether familial liability and urbanicity, an
established environmental risk factor in schizophrenia (Krabbendam and van
Os, 2005), coparticipate to cause psychosis. In this large general population
study from the Netherlands, subjects were screened for DSM-III-R psychotic
disorders and were also asked about psychotic symptoms and psychiatric treat-
ment in all first-degree relatives. Each place of residence was classified into a
five-level urbanicity rating, depending on the number of addresses within the
geographical area surrounding the residence.
As expected, both urbanicity and familial liability significantly increased the risk
for psychotic disorder. However, the effect of urbanicity was much larger in those
with familial liability. The authors estimated that 60–70% of the cases of psychosis
could be explained by the synergism between urbanicity and familial liability in
this sample. This study demonstrates the continuing utility of quantitative genetic
epidemiology in establishing possible modes of gene–environment interaction,
which may subsequently become the subject of molecular genetic studies.
Yet another putative environmental risk factor for schizophrenia, foetal hypoxia
(Clarke et al., 2006), was the subject of an interesting neuroimaging study by
Cannon et al. (2002). They examined the brain structure of subjects with schizo-
phrenia or schizoaffective disorder, their unaffected siblings and a group of healthy
unrelated controls. They also studied the hospital birth records of all the subjects
and compared the brain structures of those who had experienced obstetric com-
plications that led to foetal hypoxia. In this sample, foetal hypoxia was not more
common in patients or siblings than in controls. Foetal hypoxia was associated
with reduced grey matter and increased cerebral spinal fluid throughout the cortex
among patients and their siblings, but no such relationship existed in controls. The
existence of the relationship in the healthy siblings suggests that the effect of foetal
hypoxia on brain structure may be greater in those with a genetic liability for
schizophrenia, suggesting a classical gene–environment interaction.
In the brave new world of molecular genetic studies, one has proven particularly
fruitful in demonstrating statistical interactions between specific genes and

environments. The Dunedin birth cohort consists of around a thousand individ-
uals followed from birth through to adult life. The sample is relatively small but
remains almost intact, with 96% of the original participants taking part at
the age 26 follow-up. The study has provided evidence for gene–environment
interactions linking genes involved in neurotransmission, environmental expo-
sures during the course of development and psychiatric phenotypes. Although
only one of these relates to psychosis per se, all three shed interesting light on the
advantages and difficulties of gene–environment interactions in psychiatric
outcomes.
62 J. H. Barnett and P. B. Jones
In the first study, the authors questioned why some children who are maltreated
grow up to develop antisocial behaviour while others do not. Abnormalities in the
gene encoding monoamine oxidase A (MAOA), an enzyme that breaks down
neurotransmitters, including dopamine, noradrenalin and serotonin, have been
linked with antisocial behaviour in human beings (Brunner et al., 1993) and
aggressive behaviour in mice (Cases et al., 1995). Caspi and colleagues (2002)
hypothesised that variation in the MAOA gene might underlie the apparent
differences in antisocial behaviour seen in maltreated children. Since the MAOA
gene is located on the X chromosome it may be especially important in the
development of boys, who have only one copy.
In the Dunedin study, boys who had the high-activity form of the MAOA gene
did not show increased antisocial outcomes when exposed to childhood maltreat-
ment. However, boys with the low-activity MAOA form who were exposed to
childhood maltreatment showed increased risk for a number of antisocial out-
comes, including conduct disorder in adolescence, convictions for violence and
antisocial personality in adult life. There was a dose–response relationship such
that greater levels of maltreatment were associated with greater increases in risk for
violent outcomes.
A subsequent study has replicated this result in 514 white male twins in the USA
(Foley et al., 2004), where childhood adversity was measured in terms of inter-

parental violence, parental neglect and inconsistent discipline, and the main out-
come was conduct disorder. This study went further in attempting to determine
the nature of causality of the relationship, by examining whether it might be due to
a gene–environment correlation, rather than a true interaction. Two possible
models of correlation were suggested: an evocative one, where the child’s genotype
would affect the likelihood of experiencing adversity. This model was tested by
studying the association between the child’s exposure to adversity and maternal
antisocial personality symptoms (indicative of genetic antisocial liability). A
passive model, where an indirect influence of child’s genotype on experienced
adversity operates via correlated parental characteristics was also tested, by assess-
ing whether MAOA genotype predicted exposure to childhood adversity. In fact,
neither type of correlation could explain their findings, leading the authors to
conclude that the most likely model was a true interaction, whereby the risk
associated with MAOA genotype was qualitatively different in different
environments.
The second gene–environment interaction reported in the Dunedin sample
concerns an interaction between stressful life events, the serotonin transporter
gene and risk for depression (Caspi et al., 2003). Individuals who had experienced
more stressful life events (such as work, health or relationship stressors) in the past
five years were more likely to be depressed at age 26 and more likely to have
63 Genes and the social environment