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Genetics of Schizophrenia
Mayo Clin Proc, October 2002, Vol 77
Review
Genetics and Etiopathophysiology of Schizophrenia
JANET L. SOBELL, PHD; MARCI J. MIKESELL, PHD; AND CYNTHIA T. MCMURRAY, PHD
Schizophrenia is one of the most common, devastating, and
least understood neuropsychiatric illnesses present in the
human population. Despite decades of research involving
neurochemical, neuroanatomical, neuropathologic,
neurodevelopmental, neuropsychological, and genetic approaches, no clear etiopathophysiology has been elucidated. Among the most robust findings, however, is the
contribution of genetics to disease development. Statistical
models suggest that susceptibility to the disorder is governed by the effects of multiple genes, coupled with environmental and stochastic factors. This review briefly sum-
marizes recent etiopathologic findings and hypotheses,
with special attention to genetics.
Mayo Clin Proc. 2002;77:1068-1082
ACCx-II = anterior cingulate cortex layer II; APD = antipsychotic drug; DIRECT = direct identification of repeat expansion and cloning technique; DSM = Diagnostic and Statistical
Manual of Mental Disorders; GABA = γ-aminobutyric acid;
LOD = logarithm of the odds ratio; mRNA = messenger RNA;
PET = positron emission tomography
S
disease in terms of treatment expense and lost productivity
was estimated at more than $30 billion in 1990.2 As a
further measurement of the impact of disease, most estimates indicate that as many as a third of homeless Americans have schizophrenia.3
Despite decades of research involving neurochemical,
neuroanatomical, neuropathologic, neurodevelopmental,
neuropsychological, and genetic approaches, no clear
etiopathophysiology of schizophrenia has been elucidated.
Prevailing hypotheses involve subtle neurodevelopmental
defects that alter brain circuitry and result in aberrant
information and emotional processing. A genetic contribution to disease development is evident; however, these
effects are unlikely to be the result of a single major gene.
Rather, the interplay of multiple genes, each with small
effects, is more likely to underlie disease susceptibility.
Additional factors, including prenatal and postnatal environmental insults and random effects, are presumed to be
operative. Further genetic complexity is added by the fact
that susceptibility genes and interacting environmental
factors likely will vary among different population subgroups. Nonetheless, with use of a variety of genetic
epidemiological and molecular genetic approaches, the
identification of susceptibility genes should be possible.
Both genome-wide gene searches and targeted studies of
plausible susceptibility genes should continue. The
choice of candidate genes can be guided in part through
the findings provided by neurobiological investigations
of schizophrenia. A short review of neurobiological findings and a summary of genetic findings is provided
herein, along with a brief description of promising directions in the search for susceptibility genes.
chizophrenia is one of the most common, devastating,
and least understood neuropsychiatric illnesses afflicting the human population. Although first defined by Emil
Kraepelin and Eugen Bleuler at the turn of the 20th century,
symptoms of schizophrenia have been described throughout history and across diverse cultures, geographic locations, and socioeconomic categories. Thus, schizophrenia
is “part of the common baggage of humanity.”1 A worldwide prevalence of nearly 1% makes schizophrenia one of
the most widespread disorders known, and its impact on
affected individuals, family members, and society as a
whole would be difficult to overstate. Primarily characterized as a disorder of disrupted cognitive and emotional
processing, the disease strikes at those characteristics that
make us human. Its usual onset in early adulthood tends to
derail social relationships and interrupt educational or career plans. Coupled with the chronic nature of the cognitive
and emotional debilitation, affected individuals most often
experience lifelong occupational disability and disrupted
social relationships. In the United States alone, the cost of
From the Division of Molecular Medicine, City of Hope National
Medical Center, Duarte, Calif (J.L.S.); Department of Biochemistry
and Molecular Biology (M.J.M., C.T.M.) and Department of Molecular Pharmacology and Experimental Therapeutics (C.T.M.), Mayo
Clinic, Rochester, Minn.
This work was supported by the Mayo Foundation and the Hereditary
Disease Foundation, grants DK 43694-01A2 and MH 56207 from
the National Institutes of Health, and grant IBN 9728120 from the
National Science Foundation (C.T.M.).
Individual reprints of this article are not available. Address correspondence to Cynthia T. McMurray, PhD, Department of Molecular
Pharmacology and Experimental Therapeutics, Mayo Clinic, 200
First St SW, Rochester, MN 55905 (e-mail: mcmurray.cynthia@
mayo.edu).
Mayo Clin Proc. 2002;77:1068-1082
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© 2002 Mayo Foundation for Medical Education and Research
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Mayo Clin Proc, October 2002, Vol 77
DEFINITION AND TREATMENT
Diagnosis
Schizophrenia is a severe and chronic neuropsychiatric
disease that affects cognition, emotional processing, and
behavior. Although termed a disease, clinical heterogeneity
is marked; thus, schizophrenia is probably best described
as a symptom complex. Characteristic clinical features of
schizophrenia can be classified into 3 symptom clusters:
(1) positive or psychotic symptoms of hallucinations, delusions (including unusual thoughts and suspiciousness), and
distorted perceptions; (2) negative symptoms of flat or
blunted affect and emotions, amotivation, avolition, anhedonia, or alogia; and (3) disorganized symptoms of confused thinking, incoherence or looseness of associations in
thought and speech, and odd or bizarre behavior.4 Although
affected individuals may predominantly display signs and
symptoms of 1 cluster type, the occurrence of other symptom types is not precluded. Regardless of predominant
symptom type, a general decline in cognitive functions,
including attention, executive functions, and working
memory, is central to the behavioral disturbance and functional disability.5 As better clinical characterizations are
developed, diagnostic criteria for the disorder are updated
in the Diagnostic and Statistical Manual of Psychiatric
Disorders (DSM).6
Subtypes of schizophrenia (catatonic, disorganized,
paranoid, undifferentiated, and residual) have been described in the DSM criteria.6 However, these subtypes have
been shown “to have little diagnostic validity ... only modest stability over time and do not remain consistent within
familial groups.”7 Thus, the utility of such subtyping for
clinical, research, or other purposes is unclear.
Descriptive Epidemiology
The lifetime morbid risk of schizophrenia is approximately 1% in both men and women. However, sex differences have been reported for age at onset, premorbid functioning, clinical course, response to antipsychotic drugs
(APDs), and other disease features. Among men, the median age at onset is in the early to mid-20s, whereas onset is
3 to 5 years later in women. Recent data also suggest a
second, smaller peak in women near menopause at ages 40
to 45 years.8 Onset may be abrupt, although most individuals have an insidious onset with a variety of premorbid
symptoms. These symptoms, including social withdrawal,
diminution or loss of interest in school or work, deterioration in hygiene and grooming, and unusual behaviors, may
develop gradually over years. In general, premorbid functioning and social achievement have been reported to be
better in women.9-13 Men have been found to have more
negative or deficit symptoms than women.14-16 Among the
myriad of environmental, temporal, and other factors in-
Genetics of Schizophrenia
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vestigated for disease association, an excess of winter
births has been shown, but only for a subset of patients.4
Additionally, correlation between the occurrence of influenza epidemics and subsequent increases in rates of schizophrenia has been shown, especially when the exposure to
influenza occurred during the second trimester of gestation
when both cortical and limbic brain development are pronounced.4 However, direct evidence of viral causation or
contribution to disease development is lacking.
Treatment
Because of the chronic nature of schizophrenia, often
lifelong treatment is required. Before the advent in the
early 1950s of the APD chlorpromazine, affected individuals were sequestered by hospitalization and underwent insulin coma therapy, prefrontal lobotomy, and other dramatic, but not necessarily efficacious, treatments. From
about 1950 to the mid-1980s, several chlorpromazinerelated drugs and other drugs were introduced. Although
mechanisms of action are not completely elucidated, these
drugs appear to function primarily through the binding
of dopamine D2 receptors and are referred to as typical
APDs. The blockade of receptors in the nigrostriatal and
corticolimbic dopaminergic pathways frequently results in
extrapyramidal adverse effects, parkinsonism, or irreversible tardive dyskinesia (Figure 1).
When treated with typical APDs, approximately 30% of
individuals have been reported to be refractory to treatment. Even among responsive patients in whom overt psychotic symptoms have been ameliorated, negative disease
symptoms (eg, alogia, avolition, anhedonia) often do not
abate and occasionally appear to worsen. Whether these
negative symptoms simply are unmasked by treatment of
the positive symptoms or whether some are exacerbated or
even caused by the adverse effects of treatment is not
completely known.
In 1990, clozapine was introduced in the United States
as the prototypic atypical APD because of its reportedly
greater affinity for various subtypes of serotonin receptors
and for D4-type, rather than D2-type, dopamine receptors.
Since 1990, additional atypical APDs (eg, risperidone,
olanzapine, quetiapine, ziprasidone) have been marketed in
the United States, with many more in various stages of
clinical testing. Although these drugs hold promise to be
both more tolerable to patients (eg, no extrapyramidal adverse effects) and more effective for the amelioration of
negative and cognitive deficit symptoms in addition to
positive symptoms, these advantages remain to be shown
clearly. Atypical APDs have been associated with anticholinergic, antihistamine, and other adverse effects (eg, excessive weight gain) and, in the case of clozapine, include a
potentially fatal agranulocytosis. Controversy remains
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Genetics of Schizophrenia
Mayo Clin Proc, October 2002, Vol 77
these findings are described subsequently. Integrative hypotheses suggest that schizophrenia is a disease of disordered neural circuitry involving multiple anatomical brain
regions (eg, cortex, thalamus, basal ganglia, medial temporal lobe) and their modulation by neurotransmitter-specific
projection systems.20
Nigrostriatal pathway
Mesolimbic pathway
Mesocortical pathway
Figure 1. Major pathways of the dopamine system in the brain.
CA = caudate; NuAcc = nucleus accumbens; PFC = prefrontal
cortex; PUT = putamen; SN = substantia nigra; VTA = ventral
tegmental area.
about the optimal treatment of first episode cases,17,18 but
consensus appears to have been reached with regard to
treatment-refractory patients. For these individuals,
clozapine offers the most benefit.19
Thus, the pharmacological treatment of schizophrenia
remains empiric, with the clinician aiming to balance an
amelioration of symptoms with the occurrence of adverse
effects. The choice of APD, the decision to use any adjuvant treatments (eg, lithium, carbamazepine, benzodiazepines), and other treatment decisions often are based on
adverse effect profiles, patient’s history of response and
nonresponse, history of compliance, and other case-bycase considerations.
NEUROBIOLOGY
There is a rapidly increasing breadth and depth of data on
the brain in patients with schizophrenia, including findings
from structural and functional imaging technologies to molecular gene expression studies. A definitive pathophysiology for the disorder is far from established, with questions
remaining about whether some findings are primary or
secondary, isolated or part of a larger process, general or
specific to particular (as yet undefined) subforms of the
disorder, etc. The more robust findings and various hypotheses that have been developed based on an integration of
Neuroanatomical, Neurofunctional, and
Neurocognitive Studies
Computed tomography and magnetic resonance imaging consistently show increased volumes of the lateral and
third ventricles in schizophrenic patients. These studies
also generally show reductions in overall brain volumes of
schizophrenic patients and specific reductions in the size of
medial temporal lobe structures, such as the amygdala and
hippocampus.21 Moreover, studies have reported size decreases of the thalamus and abnormalities in midline developmental regions.22 None of these changes are specific for
schizophrenia, although some have been shown to be
present in patients with a first disease episode and no
previous medication use.
Functional neuroimaging techniques, such as positron
emission tomography (PET), provide in vivo measurements of regional glucose metabolism or cerebral blood
flow, both of which reflect regional neuronal activity.23
These techniques have allowed investigations of specific
regional metabolic abnormalities in the brains of living
schizophrenic patients either at rest or during performance of relevant functional tasks. Most of these studies
have detected changes in activity in the prefrontal cortex,
basal ganglia structures, temporolimbic regions, and
thalamus, suggesting disturbed functioning of corticostriato-thalamo-cortical circuits.24 Decreased activity in the
prefrontal cortex of schizophrenic patients is often observed during tasks of cognitive activation and working
memory.25 During active auditory hallucinations, abnormal
activation of the thalamus, striatum, limbic (especially hippocampus), and paralimbic regions has been detected.26 In
a study27 requiring recall of complex narrative material,
schizophrenic patients displayed abnormalities in prefrontal, thalamic, and cerebellar sites, suggesting disruption in
pontine-cerebellar-thalamic-frontal circuitry.
Neurochemical Studies
Historically, based on the observation that clinically
therapeutic APDs worked by binding dopamine receptors,
the dopaminergic system has been explored extensively
(Figure 1). Findings suggest that a complex dopamine
dysregulation occurs, with hyperdopaminergic activity in
the mesencephalic projections to the limbic striatum and
hypodopaminergic activity in the neocortex.5 Evidence for
hyperdopaminergic activity has included correlation be-
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Mayo Clin Proc, October 2002, Vol 77
tween the efficacy of dopamine receptor–binding drugs
and reduction in positive symptoms as well as increased D2
receptor levels in postmortem and PET studies. Recent
studies5 have suggested that various positive symptoms
correlate with abnormalities in presynaptic dopamine
storage, release, transport, and reuptake in mesolimbic
systems. Hypoactivity of dopamine systems is suggested
by findings of decreased dopamine turnover in patients
with negative symptoms,28 and in some studies29 dopamine agonists have been shown to improve negative
symptoms. Functional imaging studies30,31 also suggest that
hypofrontality is more pronounced in patients with negative symptoms.
Serotonergic, glutamatergic, and other neurotransmitter
systems (eg, γ-aminobutyric acid [GABA]) have been investigated in schizophrenia, especially in reference to interaction with dopaminergic systems. For example, lesioning
of rats with the excitotoxin kainic acid produces limbiccortical damage, including hippocampal cell loss, decreases in kainate receptors, decreases in dopamine release
in the nucleus accumbens, increases in D2-like dopamine
receptors, and an increased behavioral sensitivity to
stress.32 In studies of GABAergic systems, decreases in
glutamic acid decarboxylase, the GABA-synthesizing enzyme, have been observed in the prefrontal cortex of
schizophrenic patients,33,34 and alterations in subtypes of
GABAergic neurons have been reported. 35,36
Deficits in functional measures of sensory gating and
inhibition have been consistently reported in schizophrenic
patients and their family members.37 One of the neuronal
mechanisms responsible for such inhibitory gating involves
activation of cholinergic nicotinic receptors in the hippocampus. Stimulation of these receptors by nicotine transiently restores inhibitory gating function in schizophrenic
patients,38 which could account for the extremely high rate of
heavy smoking observed among schizophrenic patients (estimates ranging from 74% to 92% of patients compared with
30% to 35% for the general population).39 Cholinergic nicotinic receptor levels are also diminished in postmortem hippocampal tissue from some schizophrenic patients, making
this system yet another candidate for neurochemical defects
contributing to the symptoms of schizophrenia.40
The opioid system has also been considered a possible
candidate for involvement in schizophrenia, based mainly
on similarities between the pharmacological effects of
opioids and psychiatric symptoms (particularly psychotic
symptoms such as hallucinations).41 Hypotheses have been
proposed for both increased and decreased levels of various
opioid peptides as underlying factors leading to schizophrenic symptoms. However, clinical studies based on
these hypotheses have often produced variable results. For
example, some studies42 have found reductions in the cere-
Genetics of Schizophrenia
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brospinal fluid levels of enkephalin (from proenkephalin
A) in patients with chronic schizophrenia vs controls,
whereas other studies43 have reported higher levels of this
peptide in the cerebrospinal fluid of patients who received
antipsychotic medications.
Neurodevelopmental vs Neurodegenerative Findings
Several neuropathologic findings support a role for
neurodevelopmental defects in schizophrenia.44 Gliosis,
which is normally associated with adult-onset brain injuries and neurodegenerative conditions, is absent in the
brains of schizophrenic patients, indicating a developmental origin for any abnormalities. In addition, cortical cytoarchitectural anomalies have been detected in schizophrenic
patients, suggesting abnormal neuronal migration during
the second trimester of gestation.44
Integrative Hypotheses
Andreasen et al45 reviewed data from magnetic resonance imaging and PET scans in schizophrenic patients and
developed an integrated theory involving dysfunction of
cortical-subcortical-cerebellar circuitry as causative in the
disorder. Anatomical localization of specific disease symptoms has been attempted. The general conclusions from
these data are that negative symptoms may derive from
aberrations in the prefrontal cortex, auditory hallucinations
may derive from dysfunction in the temporal lobes, and
generalized thought disorder may arise from irregularities
in the planum temporale.45 Integration of these and other
findings has led to the hypothesis that the “diverse symptoms of schizophrenia reflect abnormalities in connectivity
in the circuitry that links prefrontal and thalamic regions
and where cerebro-cerebellar connectivity may also be disrupted.”45 The abnormality is presumed to be neurodevelopmental in origin, involving perhaps aberrations in
neuronal migration, cellular alignment, apoptosis, dendrite
and spine formation or pruning, or synapse formation or
deletion. Such abnormalities may be inborn (ie, genetic),
acquired (ie, environmental), or a combination of genes
and environment.
Deranged corticolimbic circuitry, resulting from alterations in brain morphologic findings, such as abnormal
arrangement and/or density of neurons in key corticolimbic
regions, also has been hypothesized as an underlying cause
of schizophrenia.46 More specifically, a shifting of cortical
dopamine afferents from pyramidal to nonpyramidal neurons in a specific brain region (anterior cingulate cortex
layer II [ACCx-II]) of schizophrenic patients is proposed as
contributing to disease symptoms. Dopamine projections
to the ACCx-II would be increased with respect to
GABAergic interneurons in this model. An inhibitory effect of dopamine on GABAergic cells would result, with
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Genetics of Schizophrenia
downstream derangements in inhibitory and disinhibitory
signals. This abnormal circuitry could play a partial role in
schizophrenia pathophysiology.46
In an additional model hypothesizing limbic-cortical
neuronal systems as key to schizophrenia, Csernansky and
Bardgett32 state that symptoms of psychosis and disorganized behavior could arise from reduced excitatory
glutamatergic inputs from the hippocampus and other limbic structures to the ventral striatum, whereas negative
symptoms could be the result of abnormal functioning of
frontal lobe structures with connections from limbic structures (eg, dorsolateral prefrontal cortex). Data from animals with limbic-cortical lesions support a decrease in
glutamatergic input to the nucleus accumbens and resulting
decreases in presynaptic dopamine release and increases in
density of dopamine D2-like receptors. Either neurodevelopmental abnormalities or later progressive lesions
could be the cause of the limbic-cortical abnormalities
observed in at least a subgroup of schizophrenic patients.32
O’Donnell and Grace30 summarized data supporting involvement of multiple interrelated systems, including the
prefrontal cortex, the medial temporal lobe (including the
hippocampus), the ventral striatum, and the mesolimbic
dopamine system, in schizophrenia. The authors contend
that the varied symptoms of schizophrenia could be the
result of “aberrant information processing in subcortical
structures that ultimately results in abnormal regulation of
cortical activity,” independent of the location of any primary lesion. Dysregulation of thalamocortical activity, in
which the thalamus provides a final common pathway for
interactions between the basal ganglia and the cortex, is
postulated as fundamental in the disease process. Abnormalities in thalamic volumes in schizophrenic patients
have been reported, although not consistently.22,47-50
Weickert and Kleinman51 also extensively reviewed
neuroanatomical (including functional studies) and neurochemical data in schizophrenia, concluding that “abnormalities in neural circuits with synaptic pathology involving the hippocampus/entorhinal cortex, the dorsolateral
prefrontal cortex, and the striatum/nucleus accumbens”
may underlie the pathophysiology of schizophrenia. Furthermore, the accumulated data suggest that “early onset,
nonprogressive, structural abnormalities in the temporal
lobe and prefrontal cortex, which are linked via pyramidal
glutamate neurons, somehow relate to a peripubertal onset
of subcortical dopaminergic abnormalities, psychosis, and
cognitive deficits.”51 Peripubertal changes in neurotransmitter systems, including dopamine, serotonin, norepinephrine, glutamate, GABA, and acetylcholine, may contribute. Reorganization of cortical connections also occurs
during the peripubertal period, with substantial regression
(pruning) of synapses. Aberrant pruning, perhaps excessive
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in some areas and inadequate in others, has been hypothesized to underlie schizophrenia.52-54 Some alterations in
correlates of synaptic connectivity (eg, levels of particular
synaptic proteins such as synaptophysin) in the brains of
schizophrenic patients have been reported.55
Emphasizing the variety of structural abnormalities in
the brains of schizophrenic patients and the increased rates
of obstetric complications and aberrant psychological and
neurologic functioning during childhood, Weickert and
Weinberger56 suggest that derangements in neurodevelopmental processes contribute to disease pathophysiology.
Abnormalities in neuronal cell proliferation, migration, or
connectivity, including axonal outgrowth, survival, synaptic regression, and myelination, may be involved. Because
these neurodevelopmental processes are fundamentally
controlled by neurodevelopmental molecules, Weickert
and Weinberger propose that the relevant genes coding
for such molecules be examined. Data on aberrant expression or function of developmentally important genes
should be integrated with findings from continued studies
of structural brain abnormalities, derangements in functional circuitry, and alterations in individual and interrelated neurotransmitter systems. Among the gene families
of importance in neurodevelopmental processes are those
involved in early pattern formation (HOX, POU family
genes), cell proliferation (FGF, EGF family genes), cell
migration (immunoglobulin family genes such as neural
cell adhesion molecule, reelin), axonal outgrowth (limbicassociated membrane protein, growth-associated protein
43), survival of connections (NGF family, nerve growth
factor), programmed cell death (BCL2 family, p53, cyclin
D), myelination (myelin basic protein, myelin-promoting
factors), and pubertal changes (estrogen and androgen
receptors).56
Lieberman57 purports that it is “widely accepted that
schizophrenia originates from abnormalities occurring during the early stages of neural development,” but argues that
data on response to therapy suggest a limited neurodegenerative process in the progression of disease. Reflecting on the fact that most patients respond to treatment
during a first episode but later may develop resistance,
Lieberman57 suggests that “ongoing deterioration” is
brought about by an underlying “degenerative process
[that] operates during the active psychotic phase of the
illness.” The degenerative process may be incremental in
addition to a fundamental neurodevelopmental deficit. Individuals with the neurodevelopmental sign of enlarged
ventricular volume are both slower to respond and less
responsive to therapy during first episode treatment compared with individuals with normal ventricular size.57,58
Likewise, patients with a history of obstetric complications
have been shown to have a poorer response to first episode
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Mayo Clin Proc, October 2002, Vol 77
therapy.59 Some investigators have found an association
between enlarged ventricles and history of obstetric complications, presumably reflecting a common underlying
cause. Thus, individuals who become nonresponsive to
therapy over time may represent a subset of patients who
have both neurodevelopmental insults and continuing
neurodegenerative processes.
Thus, clues and hypotheses regarding the pathophysiology of schizophrenia abound, but a clear and consistent
picture of underlying neuroanatomical, neurodevelopmental, and neurochemical disease mechanisms has yet to
emerge. Likewise, specific causes of the disease remain
obscure, with most evidence indicating some complex combination of genetic and environmental effects. Although
these various complex factors remain extremely difficult to
disentangle, the overwhelming evidence for a substantial
genetic contribution to schizophrenia presents an important
path forward for our understanding of the disease.
GENETICS
Family, Adoption, and Twin Studies
The classic genetic epidemiological approaches of family, twin, and adoption studies have convincingly established a significant role for genetic inheritance in the etiology of schizophrenia.60 The combined results of numerous
European family studies published from 1921 to 1987, as
summarized by Gottesman,61 clearly show an increased
risk for developing the disease in first-degree relatives of
schizophrenic patients. Compared with a lifetime risk for
schizophrenia in the general population of approximately
1%, the risk for a sibling or child of a schizophrenic parent
is approximately 10%. The risk increases further with the
number of affected relatives. For example, an individual
has a 16% risk of developing schizophrenia when both a
parent and a sibling are affected and a 46% risk when both
parents are affected. Increased risk, although still present,
decreases sharply for second- and third-degree relatives
(5% and 2%, respectively). Many of the early studies have
been criticized for methodological problems, such as
nonsystematic sampling methods, lack of standardized diagnostic criteria, absence of proper controls, and unblinded
assessments.62 More recent studies62-64 that specifically address these concerns, however, have continued to confirm
these risk estimates and show remarkably little variation
across differing samples.
Although these studies have decisively shown the familial aggregation of schizophrenia, twin and adoption studies
have provided compelling evidence that genetic factors
rather than shared family environment account for most of
this aggregation. Twin studies rely on comparison of concordance rates (extent to which both members of pairs of
twins either do or do not express a trait) between monozy-
Genetics of Schizophrenia
1073
gotic and dizygotic twins. Monozygotic twins share 100%
of their genetic material, whereas dizygotic twins share on
average 50% (as is the case for nontwin siblings), yet both
types of twins share environmental influences to approximately the same extent. Therefore, a significantly higher
rate of concordance for monozygotic than dizygotic twins
indicates genetic transmission of the disorder.
All major twin studies of schizophrenia have confirmed
this trend. Both older work, as summarized by Gottesman
and Shields,65 and more recent studies using standardized
diagnostic criteria66,67 consistently show 45% to 50%
monozygotic concordance compared with 10% to 15%
dizygotic concordance rates. Furthermore, studies of disease occurrence among the offspring of nondiscordant
monozygotic twins have shown an equally elevated risk of
disease development compared with the general population.68 The finding that the offspring of the affected
monozygotic twins would have an increased risk of disease
was expected. However, the demonstration that the offspring of the unaffected cotwins had similarly elevated
risks illustrates the phenomenon of genetic nonpenetrance
in which individuals shown or presumed to have deleterious gene(s) do not have the disease phenotype.
Several major adoption studies69-73 reported increased
rates of schizophrenia in individuals adopted from schizophrenic biological parents by healthy families compared
with control adoptees from healthy biological parents (approximately 10% vs 1%). These studies also report increased rates of disease in biological relatives of adopted
schizophrenic patients compared with adoptive relatives
and relatives of control adoptees.
Taken together, these data clearly indicate a substantial
genetic contribution to the etiology of schizophrenia, with
estimates for the overall heritability of the disease ranging
from 63% to 85%.74 The mode of inheritance, however,
remains much less clear. Obviously, the overall risks
for developing schizophrenia in different classes of relatives do not follow a pattern predicted by simple singlegene mendelian transmission. An autosomal dominant
(mendelian) mode of transmission seems to fit certain subgroups of families with multiple affected members.75 Overall, however, most single-gene models for schizophrenia do
not adequately fit the data from twin and family studies.76
The most widely accepted model for the transmission of
schizophrenia, known as the polygenic threshold model,77
describes the inheritance of a predisposition to develop the
disorder. According to this theory, the liability to develop
the disorder is normally distributed in the population, and
this distribution reflects the additive effects of several different genes plus environmental factors. Only those individuals who exceed a certain threshold of liability develop
the disease. Relatives of schizophrenic patients have on
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Genetics of Schizophrenia
average an increased liability compared with the general
population because of inherited predisposing genetic factors, causing more of these relatives to be beyond the
threshold for manifesting the disorder. This concept fits the
observed patterns of inheritance and provides explanations
for several puzzling features of schizophrenia genetics.
However, this theory remains difficult to prove in the absence of any direct links between schizophrenia and specific genes or environmental risk factors. A mixed model of
inheritance, in which 1 gene of major effect acts in combination with a background of polygenes each having a small
effect, is also not excluded by the data.
Regardless of the exact mode(s) of inheritance and role
of environmental factors in schizophrenia (or in other multifactorial disorders such as hypertension, cancer, and diabetes), the identification of susceptibility genes, each presumably of small effect, presents a daunting task. In a
recent review,78 a variety of study paradigms, including
linkage analysis and positional cloning, case-control association studies, and linkage disequilibrium approaches, are
described in terms of their optimal design, feasibility, and
statistical power. Descriptions of various study approaches
and examples of their application to the study of schizophrenia are described briefly in the following sections.
Linkage Analysis and Chromosomal Studies
Even in the absence of a known mode of inheritance,
investigators have attempted to locate genes involved in
predisposition to disease using a variety of linkage approaches. Briefly, genes on the same chromosome are
linked if inherited together more often than would be expected by chance. Among other factors, increasing physical distance between gene positions along the chromosome
(ie, gene loci) increases the probability of crossover events
occurring between them and thus decreases the chance of
their coordinated inheritance. Calculating the probability of
linkage between known chromosomal markers and disease
allows the mapping of disease-related genes to specific chromosomal regions. Positional cloning techniques then narrow
the region and eventually isolate the gene in question.
Linkage analysis has proved to be a powerful approach
for identifying an unknown causative gene by localizing it
among markers of known chromosomal position and inheritance patterns. Markers may be of several different classes
(eg, tandem repeats, single nucleotide changes) but must be
sufficiently varied between individuals so that the pattern
of inheritance can be tracked through families. As a simple
example, if all individuals with disease in an extended,
large family showed a particular marker pattern, whereas
all unaffected individuals showed a different pattern, a
candidate region for a causative gene would be in the
vicinity of the markers shared by affected individuals.
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Linkage analysis yields a probability estimate that the observed pattern of marker sharing would have occurred by
chance alone. Estimates are presented as the logarithm of
the odds ratio (LOD) score. Thus, a LOD score of 3.0
signifies 1000:1 odds in favor of linkage between an unknown gene and the marker(s), whereas a LOD score of –2.0
signifies a 100:1 odds against linkage.
Traditional methods of linkage analysis for isolating
disease-related genes have been extensively applied to
schizophrenia.79 These methods, however, were originally
devised and work best for single-gene mendelian disorders.
Linkage studies have low power to detect genes that play
only a small part in the transmission of disease, adding to
the difficulties of applying these methods to complex diseases such as schizophrenia.80 Linkage studies in schizophrenia have used a variety of sampling strategies (eg,
affected sibling pairs, nuclear families), sampling pools
(eg, geographically and ethnically isolated populations,
general population), statistical analyses (eg, parametric
in which the mode of inheritance is postulated, nonparametric in which no underlying model is assumed), disease
definitions (eg, schizophrenia only, schizophrenia and
schizoaffective disorder), disease-associated trait end
points (eg, eye tracking abnormalities, evoked auditory
potentials), and target genomic regions (eg, genome-wide,
candidate chromosomal region). Although significant
LOD scores and/or suggestive LOD scores have been reported, in general these have not been replicated consistently. Large collaborative efforts have been undertaken in
the hope of generating more conclusive results. As reviewed by Bray and Owen81 and Riley and Williamson,82
linkages with statistically significant LOD scores have
been reported from large international collaborative studies
for 22q11-q13, 6p24-p22, 8p22-p21, and 6q. Regions for
which data are suggestive but not yet fully convincing include 1q21-q22, 5q21-q31, 10p15-p11, and 13q14.1-q32.
Additionally, some investigations have shown evidence for
shared susceptibility regions (eg, 10p, 10q, 18p) between
schizophrenia and affective disorders such as bipolar disorder, whereas others have not.83-86
Chromosomal aberrations cosegregating with schizophrenia have been studied extensively in search of causative genes. A Scottish family cosegregating for a balanced
chromosomal translocation (1;11)(q42.1;q14.3) with
schizophrenia and related psychiatric disorders has been
reported.87 Two novel genes on chromosome 1 were found
to be disrupted by the translocation and have been provisionally named disrupted-in-schizophrenia 1 and 2 (DISC1
and DISC2). DISC1 encodes a large protein without significant sequence homology to other known proteins.
Based on predicted structure, the novel protein appears to
contain a globular N-terminal domain(s) and helical C-
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Mayo Clin Proc, October 2002, Vol 77
terminal domain, a structure that has the potential to form a
coiled coil by interaction with other proteins. As reported
by the authors, similar structures may be present in a variety of unrelated proteins that function in the nervous system. Interestingly, the second novel gene, DISC2, appears
to be a noncoding RNA molecule that is antisense (ie, the
complementary sequence) of DISC1 and has been hypothesized to be involved in the regulation of expression of
DISC1. The authors concluded that DISC1 and DISC2 may
represent candidate genes for susceptibility to psychiatric
illness. Whether these genes are in fact susceptibility loci
for schizophrenia needs further validation.
Genes mapping to 22q11-q13 have been of interest
based on the association of psychotic symptoms in almost
30% of individuals with the velocardiofacial syndrome.
The velocardiofacial syndrome is caused by small interstitial deletions in the 22q11 region in 80% to 85% of individuals.88 At least 1% of schizophrenic patients have been
found to have deletions in this region.89,90 Genes mapping
to the broader region that have been investigated as candidates in schizophrenia include catechol-O-methyltransferase (COMT),91 WKL1,92 ubiquitin fusion degradation 1 protein,93 tissue inhibitor of metalloproteinase 3,94 G
protein α subunit gene,95 and synapsin III.96 Some supportive yet inconclusive data have been generated. The most
widely studied gene has been COMT and particularly a G to
A nucleotide change that results in the substitution of a
methionine for valine at codon 158 in the protein product
(Val158Met). COMT represents a major degradative pathway for dopamine, and the enzyme produced with methionine has one quarter of the activity of the enzyme containing
valine. A multitude of investigations have been conducted to
determine whether the variant form of COMT is associated
with schizophrenia, subsets of schizophrenia, response to
APDs, or any other psychiatric phenotype or pharmacological response, but results have been inconclusive.91,97,98
A missense change in the WKL1 gene was reported to be
associated with periodic catatonia, a familial subtype of
catatonic schizophrenia.92 WKL1 maps to 22q13.33 and is a
putative, nonselective cation channel expressed exclusively in the brain. In the single pedigree examined, there
was a strong segregation of the mutant form of the gene
with the periodic catatonia phenotype, despite the fact that
some individuals in the family carried the mutation but
remained unaffected. Catatonia, a psychomotor disturbance
that may be akinetic and stuporous or hyperkinetic and
excited, is not specific to schizophrenia and has been observed in other psychiatric disorders.99 Although the finding
of a missense change that cosegregates with a familial subtype of schizophrenia is exciting, it also shows the difficulty of identifying genes, especially those of small effect,
in a clinically and genetically heterogeneous disorder.
Genetics of Schizophrenia
1075
An examination of 9 candidate genes within a 1.5 million–base pair (megabase) region of DNA at 22q11 has
resulted in the identification of 2 genes with evidence of
association to rare early-onset schizophrenia (before the age
of 13 years) or schizophrenia with early-onset features (deviant behaviors before the age of 10 years and schizophrenia
onset before the age of 18 years).100 Proline dehydrogenase
(PRODH2) and the DiGeorge syndrome critical region 6
genes were shown to have marker patterns that were disease
associated and replicated in different patient and control
samples. Several missense changes that may prevent synthesis of a fully functional PRODH2 enzyme were identified.
These data are intriguing and have prompted further analyses
of these genes in additional patient groups.
Candidate Gene Association Studies
The candidate gene-based association study approach
represents a complementary approach to linkage-based
analyses and is particularly well suited to detect genes of
small effect.101 These studies simply compare the frequency of specific alleles (1 of several alternative forms of
a gene or DNA sequence at a specific chromosomal position or locus) in a sample of unrelated patients with ethnically matched controls. The approach provides an additional advantage in not requiring the availability of affected
family members. Association studies may be of 2 distinct
forms, often referred to as direct or indirect studies.102 In
direct studies, candidate genes are screened for deleterious
sequence changes, which then are tested for association
with disease by comparing frequencies in affected and
unaffected individuals. The candidate gene must first be
examined extensively for sequence changes, or other polymorphism data must be available. The potential effect of
identified sequence changes on gene function must be inferred (eg, amino acid substitutions in critical protein regions, mutations that cause premature truncation of the
protein product, mutations that likely disrupt gene processing) or shown in experimental systems.
In contrast, indirect studies rely on linkage disequilibrium between markers in particular candidate genes or gene
regions and disease. Linkage disequilibrium refers to the
situation in which alleles occur together more often than
can be accounted for by chance, denoting that the alleles
are physically close on the same chromosome. The concept
is similar to that used in linkage analysis but with the
important difference that unrelated cases and controls may
be used in linkage disequilibrium studies. If the frequency
of a particular marker allele is increased in affected individuals compared with unaffected individuals, the chromosomal region around the marker(s) is more finely investigated to narrow the region and identify causative gene
mutations that cosegregate with the marker(s).
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1076
Genetics of Schizophrenia
Indirect studies have been problematic because of their
dependence both on linkage of the unknown disease gene
to a particular marker locus and presence of strong linkage
disequilibrium between causative mutation(s) in the disease gene and 1 particular marker allele. If multiple independent mutations cause disease, as is often the case for Xlinked and autosomal dominant diseases and some autosomal recessive diseases such as phenylketonuria, a single
marker allele may not always be associated with disease.
This is because some mutations may occur by chance in
chromosomes containing a particular marker allele,
whereas other mutations may occur in the chromosomes
with the other allele(s). Thus, this type of marker-based
study may produce negative results even if a correct candidate gene has been chosen. Additionally, because marker
allele frequencies may differ significantly among individuals of different ethnic backgrounds, false-positive results
can occur due to confounding,103 also referred to as population stratification.
Although linkage disequilibrium–based association
studies that rely on a limited set of markers have many
potential pitfalls, the concept still holds promise. The key
to success may be in more narrowly defining shared alleles
on the basis of multiple, densely spaced single nucleotide
polymorphisms.104,105 Single nucleotide polymorphisms are
highly abundant in the human genome, with an estimated 1
per 1000 base pairs of DNA. These biallelic markers may
be used to construct narrow haplotypes (the pattern of a
particular DNA sequence on 1 chromosome that is inherited
as a unit) more often shared by affected individuals than
unaffected individuals. If dense maps are developed, linkage
disequilibrium association analyses may become possible in
the general population, not just in isolated, inbred populations. These dense maps are under construction.
For both direct and indirect association studies, candidate genes may be selected from chromosomal regions for
which suggestive linkages have been identified, as aforementioned with reference to the chromosome 22 q11-13
region. Genes may also be selected based on known or
presumed function, pharmacological relevance, or other
biologically based criteria. Obviously, the greatest drawback of this approach is the difficulty of selecting the most
likely candidate genes for a disorder whose pathophysiology is poorly understood. Nonetheless, the various hypotheses regarding the biological mechanisms of schizophrenia
have provided clues that guide the selection of numerous
genes as potential candidates for association with disease.
Unfortunately, but not surprisingly, such candidate gene
studies for schizophrenia have thus far yielded only negative, contradictory, or unreplicated results.
Genes encoding components of the dopamine system
have historically been at the top of the list of prime candi-
Mayo Clin Proc, October 2002, Vol 77
dates for association with schizophrenia. However, numerous studies106-108 of all 5 dopamine receptor genes, as well
as other genes involved in dopamine transport or metabolism, have failed to show any clear associations with
schizophrenia. One of the more promising results has
stemmed from reports of a small increase in susceptibility
to schizophrenia associated with homozygosity for a Ser-9Gly polymorphism in the D3 receptor gene.109 However,
more recent work has failed to replicate this finding.110
Genes involved in other neurotransmitter systems
known to interact with dopamine pathways or otherwise
implicated in the biochemistry of schizophrenia, as well as
several genes important in neurodevelopment, also have
been explored in association studies. Among these various
genes tested, a few promising leads have been uncovered.
For example, weak association with disease has been
shown for the nerve growth factor neurotrophin 3 in some
studies,111 although not others.112 A C to T silent polymorphism in the serotonin receptor gene (most likely in linkage
disequilibrium with an unidentified functional variant)
has also been linked to disease in some reports.113 Interestingly, this polymorphism seems to predict response to
clozapine,114,115 although this finding also awaits replication. Genes encoding various subunits of glutamate receptors also have been examined for association with disease
or pharmacological response, without major positive findings.116-119 Other genes that have been investigated extensively but for which strong disease associations have not
been consistently found include developmentally related
genes such as NOTCH4,120-123 ion channel genes such as
hSKCa3, KCNN3, GLRA2, and the α-7 nicotinic receptor,124-128 as well as a variety of genes in the major histocompatibility complex.129 Many of the investigated genes
contain short repetitive DNA sequences, known as trinucleotide repeats, as described more fully in the following
section.
Trinucleotide Repeat Analyses
An additional model for the genetic transmission of
schizophrenia has arisen from the identification of a new
class of human mutation–heritable unstable DNA. In the
human genome, repetitive DNA sequences are abundant.
Certain types of these repetitive sequences (eg, those containing multiple repeats of a 3 DNA base [trinucleotide]
unit such as CAG or CCG) are inherently unstable, and
both expansions and contractions of the number of repeating 3 base units can occur. The significant expansion
of specific trinucleotide repeat sequences has been discovered as the underlying cause of several neurologic or
neurodegenerative diseases, including Huntington disease,
myotonic dystrophy, and types of spinocerebellar ataxia
and fragile X syndrome. Importantly, this trinucleotide
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Mayo Clin Proc, October 2002, Vol 77
repeat expansion was proved to be the biological basis of
the clinically observed phenomenon known as genetic anticipation, which is characterized by an earlier age at onset
and increased severity of illness in successive generations
of affected individuals.130
Anticipation was originally described for families with
psychosis and mental retardation at the turn of the century131 and was subsequently observed in other neurologic
diseases, such as Huntington disease and myotonic dystrophy. This clinical feature was dismissed for many decades,
however, as a statistical artifact resulting from ascertainment bias.132 Ascertainment biases that lead to incorrect
conclusions of anticipation can arise for several reasons.
For example, reduced reproductive fitness in individuals
with severe early-onset illness results in the preferential
selection of parents with later disease onset. Children with
younger age at onset can also be overrepresented in the
sample because these more severe cases are more likely to be
treated and identified for study. The recruitment of affected
parent-offspring pairs during a limited time frame favors the
selection of pairs with parents with later-onset disease and
offspring with early-onset disease because the offspring may
not have had time to develop late-onset disease.
Nevertheless, the advent of modern molecular biology
techniques provided conclusive evidence for the occurrence of true genetic anticipation in certain neurologic
diseases. These methods uncovered the molecular equivalent of anticipation in the form of trinucleotide repeat expansions. For diseases linked to genes containing these
repeat expansions, the degree of expansion varies across
generations of affected families and correlates with clinical
symptoms. An increase in the number of trinucleotide repeats correlates with an increase in the severity of the
disorder and a decrease in the age at onset in younger
generations. This finding has rekindled interest in reports
of anticipation observed in families showing strong inheritance of neuropsychiatric diseases, such as schizophrenia
and bipolar disorder.
Reevaluation of the inheritance patterns of major psychoses has suggested that the unstable DNA model represents a good fit for the twin and family epidemiological
data of schizophrenia and affective disorders.133 In fact, this
model competes well with the traditional multifactorial
polygenic theory, and the nonmendelian behavior of unstable DNA could explain some of the complex, unresolved facets of psychiatric genetics. For example, unstable
DNA can exist in a premutation form, in which the number
of repeats is higher than normal but just below the disease
threshold, and can undergo somatic mutation in early embryogenesis. These factors could account for the puzzling
observation of identical rates of schizophrenia in the offspring of discordant monozygotic twins.68 If the initial
Genetics of Schizophrenia
1077
Figure 2. Pedigree of schizophrenia family displaying anticipation. This representative pedigree from the study of Bassett and
Honer135 shows the occurrence of anticipation in 8 Eastern Canadian schizophrenia families. GG = grandparental generation; IG =
index generation; PG = parental generation. Numbers below each
individual indicate their age in years at first hospitalization for
psychotic illness. Closed symbols indicate affected individuals;
half-closed symbols indicate the presence of schizotypal conditions; open symbols indicate unaffected individuals.
inherited repeat number was just below the threshold for
disease, then unequal amounts of expansion could lead to
disease in 1 twin but not the other. Further repeat expansion
in the offspring of the unaffected twin could then lead to the
expression of the disease in that individual as well.
However, the complex nature of schizophrenia and its
inheritance have impeded the task of definitively demonstrating the occurrence of true genetic anticipation in this
disease. Nonetheless, evidence for anticipation in some
families displaying strong aggregation of schizophrenia
continues to mount.134 Several recent studies of families
with multiple affected members have been conducted to
test for anticipation while specifically addressing the major
sources of ascertainment bias. For example, 1 study135 investigated 8 Eastern Canadian families (186 total members) with many schizophrenic relatives for the presence of
anticipation. This study found significant decreases in age
at onset and increased severity across generations. Figure 2
shows a representative pedigree for one of these families.
Overall, the study reported a mean age at first hospitalization of 41 years for the grandparental generation, 34 years
for the parental generation, and 26 years for the index
generation. An increase in the severity of disease was also
observed based on rates of hospitalization for psychosis
and the proportion of such hospitalizations compared with
schizotypal conditions across successive generations.
These results have been confirmed by various additional
studies analyzing large numbers of European and Ameri-
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1078
Genetics of Schizophrenia
can families and using similar methods to limit ascertainment biases.134,136,137 A reanalysis of archival data from the
extensive familial mental illness study by Penrose has also
given weight to the argument for true anticipation. This
study was able to control for ascertainment bias by taking
advantage of a large data set (7339 individuals from 3109
families) ascertained during an extended time frame (70
years) and including aunt/uncle–niece/nephew pairs of affected individuals in addition to parent-offspring pairs.138,139
Therefore, the growing consensus that true genetic anticipation occurs in at least some highly familial forms of
schizophrenia has heightened interest in the unstable DNA
hypothesis. According to this hypothesis, a still unidentified trinucleotide repeat expansion, either singly or in combination with other genetic factors, may account for the
inheritance of schizophrenia. This adds yet another approach
to searching for specific genes associated with this disease.
Finally, evidence for genetic anticipation in families of
schizophrenic patients has led to the development and
implementation of novel molecular approaches for identifying genes associated with schizophrenia. The long
stretches of trinucleotide repeats associated with anticipation provide a specific feature of DNA with defined sequences for which to look. This gives methods targeted
toward these sequences distinct advantages over standard
linkage mapping techniques. Furthermore, searching specifically for genes containing trinucleotide repeat expansions would require no a priori knowledge of pathophysiology, in contrast to candidate gene–based approaches. If the
underlying hypothesis is correct, then methods aimed at
detecting these long repetitive sequences in the genome,
isolating the genes containing these sequences, and assessing size expansion in association with disease may shed
new light on genetic mechanisms of schizophrenia.
Preliminary support for the presence of expanded trinucleotide repeat sequences in the DNA of schizophrenic
patients has been reported. With use of a method referred to
as repeat expansion detection analysis,140 significant shifts
in the distribution of CTG repeats have been shown in
groups of schizophrenic patients compared with controls,
with the patient group having evidence of expansions.141-143
However, increases were modest and overlapped with the
size of repeats found in unaffected individuals. Also, although the repeat expansion detection technique is able to
detect the presence of expanded repeats, no information is
provided on the underlying gene(s) in which the expansion
occurred or the gene(s) chromosomal location.
With a view toward identifying genes containing trinucleotide repeat expansions, other methods have been
developed and implemented in large screening efforts.
Lists of novel CAG repeat–containing genes have been compiled as potential candidates for association studies.144-146
Mayo Clin Proc, October 2002, Vol 77
However, these studies are limited in their specificity for
expanded vs normal repeats, in the type of repeat that can
be detected (ie, CAGs), and in their ability to detect repeats
located within coding regions of genes only. Repeat expansions within the nonprotein coding portions of the gene
(introns) have been shown to cause disease (eg, GAA
repeat expansion in intron 1 of the frataxin gene causing
Friedreich ataxia).147
To overcome some of these difficulties, a method was
developed to directly detect and then identify the gene
containing repeat expansions directly from the DNA of
patients. This method, termed DIRECT for direct identification of repeat expansion and cloning technique, was used
to successfully identify a CAG repeat expansion causing
spinocerebellar ataxia type 2.148 The DIRECT technique
could potentially be applied to the detection of other pathologic repeat expansions. The approach has definite advantages for schizophrenia studies in that it requires no prior
knowledge of chromosomal locations or pathologic functions of causative genes. Limitations include the amount of
sample DNA needed for adequate sensitivity and a variable
ability to unequivocally identify disease-specific repeat expansions from amid multiple repeat sequences found in
both healthy and diseased individuals. Thus, the ability to
adequately resolve the deleterious, disease-related expansions depends on multiple experimental design factors, the
sizes of repeat expansions, and other parameters.
Gene Expression Studies
A recently developed genetic strategy is that of gene
expression analysis. Through expression analysis, a profile
of which genes are activated at which time and at what
levels can ultimately be obtained. If differences in gene
expression levels are identified between diseased and
healthy individuals, the involved genes may represent candidates for disease causation, progression, response to
therapy, or other factors, depending on the experimental
design. A variety of techniques are available for the analysis of gene expression patterns, including arrays in which
the messenger RNA (mRNA) for tens of thousands of
genes may be simultaneously measured from target tissue.
Messenger RNA is the single-stranded template that is
produced (transcribed) from a gene’s DNA as an intermediate step for those genes coding for protein products
(translation). However, expressed genes include not only
those that are transcribed and then translated into protein
but also those that are transcribed into RNA but not translated into protein (eg, transfer and ribosomal RNAs).
In studies of schizophrenia, postmortem brain tissue
from particular regions (eg, hippocampus, thalamus, prefrontal cortex) of diseased and healthy individuals (usually
matched for age, sex, time from death to tissue analysis,
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Mayo Clin Proc, October 2002, Vol 77
tissue preparation techniques, and other variables) has been
analyzed. In a recently published study149 using prefrontal
cortex samples from matched pairs of patients with schizophrenia and control subjects, mRNA transcripts encoding
proteins involved in the regulation of presynaptic function
were decreased in all patients with schizophrenia. These
genes also displayed a different combination of decreased
expression in these patients. When other genes not involved in presynaptic function were evaluated, no alterations in expression were found. Selected presynaptic function gene microarray observations were verified by other
experiments that used alternate approaches. Two genes
demonstrating the most consistently altered mRNA expression levels were N-ethylmaleimide–sensitive factor and
synapsin II. Both are involved in presynaptic functioning,
and the authors concluded that the combined data suggested that patients with schizophrenia share a common
abnormality in presynaptic function. Increased expression
of genes encoding synaptic glutamatergic transporters in
thalami from schizophrenic patients compared with controls also has been reported.150 In other studies of thalamic
nuclei in schizophrenic patients and controls, altered
ionotropic glutamate receptor binding and reduced
mRNA expression levels in the thalamus were reported for
various subunit genes, including NMDAR1, NMDAR2B,
NMDAR2C, gluR1, gluR3, and KA2. The authors noted that
the differences were most prominent in nuclei with reciprocal projections to limbic regions.151 The observed abnormalities in N-methyl-D-aspartate, 2-amino-3-hydroxy-5methyl-4-isoxazole proprionic acid, and kainate receptor
expression in limbic thalamus were suggestive of an Nmethyl-D-aspartate receptor hypoactivity in schizophrenia
and were consistent with diminished glutamatergic activity
in the thalamus. Alternatively, the results could suggest
abnormal glutamatergic innervation in afferent and/or efferent regions. In an analysis of prefrontal cortex tissue, upregulation of apolipoprotein genes L1, L2, and L4 was
shown and replicated in additional samples from schizophrenic patients from distinct populations (Japan and New
Zealand).152 The apolipoprotein gene cluster (L1-L6) has
been mapped to chromosome 22q12.3, a region previously
linked in some studies of schizophrenia and near the deletion region in VCFS (22q11).
Expression analysis, although extremely valuable as yet
another approach to identifying candidate genes, is limited
by the availability of appropriate target tissue, its temporal
nature (genes expressed at the time of death), genes represented on the array, and other factors, including the possible effects of antipsychotic medication on gene expression. The application of gene expression analysis to animal
models of aberrant behavior, in which multiple experimental parameters may be controlled, may yield insights into
Genetics of Schizophrenia
1079
patterns of gene expression during development and puberty, antipsychotic treatment, stressful conditions, and
other paradigms. Not only may particular candidate genes
be identified but also entire pathways of sequential and
coordinated gene expression may be elucidated for intensive study in schizophrenic patients.
SUMMARY AND FUTURE DIRECTIONS
Despite clear evidence for a genetic contribution to the
development of schizophrenia, previously tested hypotheses and current methods have thus far failed to convincingly identify specific genetic factors that cause or predispose individuals to the disorder. We hope that active
research in neuroanatomy, functional neuroanatomy, neuropathology, neurochemistry, neuropsychology, neurodevelopment, molecular neuroscience, and molecular epidemiology will provide clues about underlying pathophysiology
and gene systems of interest. Heterogeneity of the underlying genetic and etiologic factors is the expectation, with
neurodevelopmental and possibly neurodegenerative processes involved. Suspect candidate genes, either currently
known or yet to be identified, may play a role not only in
disease development and progression but also in the mediation of response to therapy.
REFERENCES
1. Berrios GE. The History of Mental Symptoms: Descriptive Psychopathology Since the Nineteenth Century. Cambridge, England:
Cambridge University Press; 1996:35.
2. Rupp A, Keith SJ. The costs of schizophrenia: assessing the burden.
Psychiatr Clin North Am. 1993;16:413-423.
3. Bachrach LL. What we know about homelessness among mentally
ill persons: an analytical review and commentary. In: Lamb HR,
Bachrach LL, Kass FI, eds. Treating the Homeless Mentally Ill.
Washington, DC: American Psychiatric Association; 1992:13-40.
4. Pinals DA, Breier A. Schizophrenia. In: Tasman A, Kay J,
Lieberman JA, eds. Psychiatry. Vol 2. Philadelphia, Pa: WB
Saunders Co; 1997:927-965.
5. Lewis DA, Lieberman JA. Catching up on schizophrenia: natural
history and neurobiology. Neuron. 2000;28:325-334.
6. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders: DSM-IV. 4th ed. Washington, DC:
American Psychiatric Association; 1994.
7. Hyman SE. Schizophrenia. In: Rubenstein E, Federman DD, eds.
Scientific American Medicine. Vol 3. Chapter 13, Section VII. New
York, NY: Scientific American, Inc; 2000.
8. Hafner H, an der Heiden W. Epidemiology of schizophrenia. Can J
Psychiatry. 1997;42:139-151.
9. McGlashan TH, Bardenstein KK. Gender differences in affective,
schizoaffective, and schizophrenic disorders. Schizophr Bull. 1990;
16:319-329.
10. Shtasel DL, Gur RE, Gallacher F, Heimberg C, Gur RC. Gender
differences in the clinical expression of schizophrenia. Schizophr
Res. 1992;7:225-231.
11. Bromet EJ, Dew MA, Parkinson DK, Cohen S, Schwartz JE. Effects of occupational stress on the physical and psychological
health of women in a microelectronics plant. Soc Sci Med. 1992;
34:1377-1383.
12. Andia AM, Zisook S, Heaton RK, et al. Gender differences in
schizophrenia. J Nerv Ment Dis. 1995;183:522-528.
13. Larsen TK, McGlashan TH, Moe LC. First-episode schizophrenia,
I: early course parameters. Schizophr Bull. 1996;22:241-256.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1080
Genetics of Schizophrenia
14. Szymanski S, Lieberman JA, Alvir JM, et al. Gender differences in
onset of illness, treatment response, course, and biologic indexes in
first-episode schizophrenic patients. Am J Psychiatry.
1995;152:698-703.
15. Cowell PE, Kostianovsky DJ, Gur RC, Turetsky BI, Gur RE. Sex
differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry. 1996;153:799-805.
16. Gur RE, Petty RG, Turetsky BI, Gur RC. Schizophrenia throughout
life: sex differences in severity and profile of symptoms. Schizophr
Res. 1996;21:1-12.
17. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical
antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ. 2000;321:1371-1376.
18. Kapur S, Remington G. Atypical antipsychotics [editorial]. BMJ.
2000;321:1360-1361.
19. Bustillo JR, Lauriello J, Keith SJ. Schizophrenia: improving outcome. Harv Rev Psychiatry. 1999;6:229-240.
20. Goff DC, Heckers S, Freudenreich O. Schizophrenia. Med Clin
North Am. 2001;85:663-689.
21. Lawrie SM, Abukmeil SS. Brain abnormality in schizophrenia: a
systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry. 1998;172:110-120.
22. Andreasen NC. The role of the thalamus in schizophrenia. Can J
Psychiatry. 1997;42:27-33.
23. Buchsbaum MS. Positron-emission tomography and regional brain
metabolism in schizophrenia research. In: Volkow ND, Wolf AP,
eds. Positron-Emission Tomography in Schizophrenia Research.
Washington, DC: American Psychiatric Press; 1991:27-46.
24. Siegel BV Jr, Buchsbaum MS, Bunney WE Jr, et al. Corticalstriatal-thalamic circuits and brain glucose metabolic activity in 70
unmedicated male schizophrenic patients. Am J Psychiatry.
1993;150:1325-1336.
25. Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of
dorsolateral prefrontal cortex in schizophrenia, I: regional cerebral
blood flow evidence. Arch Gen Psychiatry. 1986;43:114-124.
26. Silbersweig DA, Stern E, Frith C, et al. A functional neuroanatomy
of hallucinations in schizophrenia. Nature. 1995;378:176-179.
27. Andreasen NC, O’Leary DS, Cizadlo T, et al. Schizophrenia and
cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proc Natl Acad
Sci U S A. 1996;93:9985-9990.
28. Rao ML, Moller HJ. Biochemical findings of negative symptoms in
schizophrenia and their putative relevance to pharmacologic treatment: a review. Neuropsychobiology. 1994;30:160-172.
29. Sanfilipo M, Wolkin A, Angrist B, et al. Amphetamine and negative symptoms of schizophrenia. Psychopharmacology (Berl).
1996;123:211-214.
30. O’Donnell P, Grace AA. Dysfunctions in multiple interrelated
systems as the neurobiological bases of schizophrenic symptom
clusters. Schizophr Bull. 1998;24:267-283.
31. Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry. 2001;58:165-171.
32. Csernansky JG, Bardgett ME. Limbic-cortical neuronal damage
and the pathophysiology of schizophrenia. Schizophr Bull. 1998;
24:231-248.
33. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA. Decreased glutamic acid decarboxylase67 messenger RNA expression
in a subset of prefrontal cortical gamma-aminobutyric acid neurons
in subjects with schizophrenia. Arch Gen Psychiatry. 2000;57:237245.
34. Costa E, Pesold C, Auta J, et al. Reelin and GAD67 downregulation
and psychosis vulnerability. Biol Psychiatry. 2000;47(suppl
1):S68.
35. Reynolds GP, Zhang ZJ, Beasley CL. Neurochemical correlates of
cortical GABAergic deficits in schizophrenia: selective losses of
calcium binding protein immunoreactivity. Brain Res Bull.
2001;55:579-584.
36. Pierri JN, Chaudry AS, Woo TU, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic
subjects. Am J Psychiatry. 1999;156:1709-1719.
37. Braff DL, Swerdlow NR, Geyer MA. Gating and habituation deficits in the schizophrenia disorders. Clin Neurosci. 1995;3:131-139.
Mayo Clin Proc, October 2002, Vol 77
38. Adler LE, Hoffer LJ, Griffith J, Waldo MC, Freedman R. Normalization by nicotine of deficient auditory sensory gating in the
relatives of schizophrenics. Biol Psychiatry. 1992;32:607-616.
39. Goff DC, Henderson DC, Amico E. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry. 1992;149:1189-1194.
40. Freedman R, Adler LE, Bickford P, et al. Schizophrenia and nicotinic receptors. Harv Rev Psychiatry. 1994;2:179-192.
41. Wiegant VM, Ronken E, Kovacs G, De Wied D. Endorphins and
schizophrenia. Prog Brain Res. 1992;93:433-453.
42. Wen HL, Lo CW, Ho WK. Met-enkephalin level in the cerebrospinal fluid of schizophrenic patients. Clin Chim Acta. 1983;128:367371.
43. Kleine TO, Klempel K, Funfgeld EW. Methionine(Met)-enkephalin and leucine(Leu)-enkephalin in CSF of chronic schizophrenics:
correlation with psychopathology. Protides Biological Fluids.
1984;32:175-178.
44. Weinberger DR. From neuropathology to neurodevelopment. Lancet. 1995;346:552-557.
45. Andreasen NC, Paradiso S, O’Leary DS. “Cognitive dysmetria” as
an integrative theory of schizophrenia: a dysfunction in corticalsubcortical-cerebellar circuitry? Schizophr Bull. 1998;24:203-218.
46. Benes FM. Model generation and testing to probe neural circuitry
in the cingulate cortex of postmortem schizophrenic brain.
Schizophr Bull. 1998;24:219-230.
47. Pakkenberg B. Pronounced reduction of total neuron number in
mediodorsal thalamic nucleus and nucleus accumbens in
schizophrenics. Arch Gen Psychiatry. 1990;47:1023-1028.
48. Andreasen NC, Arndt S, Swayze V II, et al. Thalamic abnormalities
in schizophrenia visualized through magnetic resonance image averaging. Science. 1994;266:294-298.
49. Jones EG. Cortical development and thalamic pathology in schizophrenia. Schizophr Bull. 1997;23:483-501.
50. Wolkin A, Rusinek H, Vaid G, et al. Structural magnetic resonance
image averaging in schizophrenia. Am J Psychiatry. 1998;155:
1064-1073.
51. Weickert CS, Kleinman JE. The neuroanatomy and neurochemistry
of schizophrenia. Psychiatr Clin North Am. 1998;21:57-75.
52. Huttenlocher PR. Synaptic density in human frontal cortex-developmental changes and effects of aging. Brain Res. 1979;163:195205.
53. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res. 1982-83;17:319334.
54. Keshavan MS, Bagwell WW, Haas GL, Sweeney JA, Schooler NR,
Pettegrew JW. Changes in caudate volume with neuroleptic treatment [letter]. Lancet. 1994;344:1434.
55. Lewis DA. Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia.
Neuropsychopharmacology. 1997;16:385-398.
56. Weickert CS, Weinberger DR. A candidate molecule approach to
defining developmental pathology in schizophrenia. Schizophr
Bull. 1998;24:303-316.
57. Lieberman JA. Pathophysiologic mechanisms in the pathogenesis
and clinical course of schizophrenia. J Clin Psychiatry. 1999;
60(suppl 12):9-12.
58. Lieberman J, Jody D, Geisler S, et al. Time course and biologic
correlates of treatment response in first-episode schizophrenia.
Arch Gen Psychiatry. 1993;50:369-376.
59. Alvir JM, Woerner MG, Gunduz H, Degreef G, Lieberman JA.
Obstetric complications predict treatment response in first-episode
schizophrenia. Psychol Med. 1999;29:621-627.
60. McGuffin P, Owen MJ, Farmer AE. Genetic basis of schizophrenia.
Lancet. 1995;346:678-682.
61. Gottesman II. Schizophrenia Genesis: The Origins of Madness.
New York, NY: WH Freeman; 1991.
62. Kendler KS, Diehl SR. The genetics of schizophrenia: a current,
genetic-epidemiologic perspective. Schizophr Bull. 1993;19:261285.
63. Kendler KS, Gruenberg AM, Tsuang MT. Psychiatric illness in
first-degree relatives of schizophrenic and surgical control patients:
a family study using DSM-III criteria. Arch Gen Psychiatry.
1985;42:770-779.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, October 2002, Vol 77
64. Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman M,
Walsh D. The Roscommon Family Study I: methods, diagnosis of
probands, and risk of schizophrenia in relatives. Arch Gen Psychiatry. 1993;50:527-540.
65. Gottesman II, Shields J. Schizophrenia, the Epigenetic Puzzle.
Cambridge, England: Cambridge University Press; 1982.
66. Farmer AE, McGuffin P, Gottesman II. Twin concordance and
DSM-III schizophrenia: scrutinizing the validity of the definition.
Arch Gen Psychiatry. 1987;44:634-641.
67. Onstad S, Skre I, Torgersen S, Kringlen E. Twin concordance for
DSM-III-R schizophrenia. Acta Psychiatr Scand. 1991;83:395-401.
68. Gottesman II, Bertelsen A. Confirming unexpressed genotypes for
schizophrenia: risks in the offspring of Fischer’s Danish identical and
fraternal discordant twins. Arch Gen Psychiatry. 1989;46:867-872.
69. Heston LL. Psychiatric disorders in foster home reared children of
schizophrenic mothers. Br J Psychiatry. 1966;112:819-825.
70. Kety SS. Mental illness in the biological and adoptive relatives of
schizophrenic adoptees: findings relevant to genetic and environmental factors in etiology. Am J Psychiatry. 1983;140:720-727.
71. Lowing PA, Mirsky AF, Pereira R. The inheritance of schizophrenia spectrum disorders: a reanalysis of the Danish adoptee study
data. Am J Psychiatry. 1983;140:1167-1171.
72. Kety SS, Wender PH, Jacobsen B, et al. Mental illness in the
biological and adoptive relatives of schizophrenic adoptees: replication of the Copenhagen Study in the rest of Denmark. Arch Gen
Psychiatry. 1994;51:442-455.
73. Tienari P. Interaction between genetic vulnerability and family
environment: the Finnish adoptive family study of schizophrenia.
Acta Psychiatr Scand. 1991;84:460-465.
74. McGuffin P, Asherson P, Owen M, Farmer A. The strength of the
genetic effect: is there room for an environmental influence in the
aetiology of schizophrenia? Br J Psychiatry. 1994;164:593-599.
75. Kaufmann CA, Monto A, Young GS, et al. Does early onset characterize autosomal dominant schizophrenia? [abstract]. Schizophr
Res. 1993;9:118-119.
76. Risch N. Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol. 1990;7:3-16.
77. Gottesman II, Shields J. A polygenic theory of schizophrenia. Proc
Natl Acad Sci U S A. 1967;58:199-205.
78. Risch NJ. Searching for genetic determinants in the new millennium. Nature. 2000;405:847-856.
79. Moldin SO. The maddening hunt for madness genes. Nat Genet.
1997;17:127-129.
80. Kirov G, Murray R. The molecular genetics of schizophrenia:
progress so far. Mol Med Today. 1997;3:124-130.
81. Bray NJ, Owen MJ. Searching for schizophrenia genes. Trends Mol
Med. 2001;7:169-174.
82. Riley B, Williamson R. Sane genetics for schizophrenia. Nat Med.
2000;6:253-255.
83. Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD. Do
schizophrenia and affective disorder share susceptibility genes?
Schizophr Res. 1999;39:107-111.
84. Nancarrow DJ, Levinson DF, Taylor JM, et al. No support for
linkage to the bipolar regions on chromosomes 4p, 18p, or 18q in
43 schizophrenia pedigrees. Am J Med Genet. 2000;96:224-227.
85. Kelsoe JR, Spence MA, Loetscher E, et al. A genome survey
indicates a possible susceptibility locus for bipolar disorder on
chromosome 22. Proc Natl Acad Sci U S A. 2001;98:585-590.
86. Berrettini WH. Are schizophrenic and bipolar disorders related? a
review of family and molecular studies. Biol Psychiatry. 2000;
48:531-538.
87. Millar JK, Wilson-Annan JC, Anderson S, et al. Disruption of two
novel genes by a translocation co-segregating with schizophrenia.
Hum Mol Genet. 2000;9:1415-1423.
88. Jurewicz I, Owen RJ, O’Donovan MC, Owen MJ. Searching for
susceptibility genes in schizophrenia. Eur Neuropsychopharmacol.
2001;11:395-398.
89. Arinami T, Ohtsuki T, Takase K, et al. Screening for 22q11 deletions in a schizophrenia population. Schizophr Res. 2001;52:167170.
90. Murphy KC, Owen MJ. Velo-cardio-facial syndrome: a model for
understanding the genetics and pathogenesis of schizophrenia. Br J
Psychiatry. 2001;179:397-402.
Genetics of Schizophrenia
1081
91. Ohmori O, Shinkai T, Kojima H, et al. Association study of a
functional catechol-O-methyltransferase gene polymorphism in
Japanese schizophrenics. Neurosci Lett. 1998;243:109-112.
92. Meyer J, Huberth A, Ortega G, et al. A missense mutation in a
novel gene encoding a putative cation channel is associated with
catatonic schizophrenia in a large pedigree. Mol Psychiatry.
2001;6:302-306.
93. De Luca A, Pasini A, Amati F, et al. Association study of a
promoter polymorphism of UFD1L gene with schizophrenia. Am J
Med Genet. 2001;105:529-533.
94. Hung CC, Chen YH, Tsai MT, Chen CH. Systematic search for
mutations in the human tissue inhibitor of metalloproteinases-3
(TIMP-3) gene on chromosome 22 and association study with
schizophrenia. Am J Med Genet. 2001;105:275-278.
95. Saito T, Papolos DF, Chernak D, Rapaport MH, Kelsoe JR,
Lachman HM. Analysis of GNAZ gene polymorphism in bipolar
affective disorder. Am J Med Genet. 1999;88:324-328.
96. Kao HT, Porton B, Czernik AJ, et al. A third member of the synapsin
gene family. Proc Natl Acad Sci U S A. 1998;95:4667-4672.
97. Karayiorgou M, Gogos JA, Galke BL, et al. Identification of sequence variants and analysis of the role of the catechol-O-methyltransferase gene in schizophrenia susceptibility. Biol Psychiatry.
1998;43:425-431.
98. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT
Val108/158 Met genotype on frontal lobe function and risk for
schizophrenia. Proc Natl Acad Sci U S A. 2001;98:6917-6922.
99. Mirnics K, Lewis DA. Genes and subtypes of schizophrenia.
Trends Mol Med. 2001;7:281-283.
100. Liu H, Heath SC, Sobin C, et al. Genetic variation at the 22q11
PRODH2/DGCR6 locus presents an unusual pattern and increases
susceptibility to schizophrenia. Proc Natl Acad Sci U S A. 2002;
99:3717-3722.
101. Sobell JL, Heston LL, Sommer SS. Novel association approach for
determining the genetic predisposition to schizophrenia: case-control resource and testing of a candidate gene. Am J Med Genet.
1993;48:28-35.
102. Collins FS, Guyer MS, Charkravarti A. Variations on a theme:
cataloging human DNA sequence variation. Science. 1997;278:
1580-1581.
103. Schlesselman JJ. Case-control Studies: Design, Conduct, Analysis.
New York, NY: Oxford University Press; 1982.
104. Lander ES. The new genomics: global views of biology. Science.
1996;274:536-539.
105. Kruglyak L. Prospects for whole-genome linkage disequilibrium
mapping of common disease genes. Nat Genet. 1999;22:139-144.
106. Gejman PV, Ram A, Gelernter J, et al. No structural mutation in the
dopamine D2 receptor gene in alcoholism or schizophrenia: analysis using denaturing gradient gel electrophoresis. JAMA. 1994;
271:204-208.
107. Kendler KS. Overview: a current perspective on twin studies of
schizophrenia. Am J Psychiatry. 1983;140:1413-1425.
108. Asherson P, Mant R, McGuffin P. Genetics and schizophrenia. In:
Hirsh SR, Weinberger DR, eds. Schizophrenia. Oxford, England:
Blackwell Science; 1995:253-274.
109. Shaikh S, Collier DA, Sham PC, et al. Allelic association between a
Ser-9-Gly polymorphism in the dopamine D3 receptor gene and
schizophrenia. Hum Genet. 1996;97:714-719.
110. Malhotra AK, Goldman D, Buchanan RW, et al. The dopamine D3
receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response.
Mol Psychiatry. 1998;3:72-75.
111. Jonsson E, Brene S, Zhang XR, et al. Schizophrenia and
neurotrophin-3 alleles. Acta Psychiatr Scand. 1997;95:414-419.
112. Gill M, Hawi Z, O’Neill FA, Walsh D, Straub RE, Kendler KS.
Neurotrophin-3 gene polymorphisms and schizophrenia: no evidence for linkage or association. Psychiatr Genet. 1996;6:183-186.
113. Williams J, Spurlock G, McGuffin P, et al, European Multicentre
Association Study of Schizophrenia (EMASS) Group. Association
between schizophrenia and T102C polymorphism of the 5-hydroxytryptamine type 2a-receptor gene. Lancet. 1996;347:1294-1296.
114. Arranz M, Collier D, Sodhi M, et al. Association between clozapine
response and allelic variation in 5-HT2A receptor gene. Lancet.
1995;346:281-282.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1082
Genetics of Schizophrenia
115. Arranz MJ, Munro J, Owen MJ, et al. Evidence for association
between polymorphisms in the promoter and coding regions of the
5-HT2A receptor gene and response to clozapine. Mol Psychiatry.
1998;3:61-66.
116. Rice SR, Niu N, Berman DB, Heston LL, Sobell JL. Identification
of single nucleotide polymorphisms (SNPs) and other sequence
changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients. Mol Psychiatry. 2001;6:274-284.
117. Hong CJ, Yu YW, Lin CH, Cheng CY, Tsai SJ. Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and
psychopathology and clozapine response in schizophrenia.
Psychiatr Genet. 2001;11:219-222.
118. Ohtsuki T, Toru M, Arinami T. Mutation screening of the
metabotropic glutamate receptor mGluR4 (GRM4) gene in patients
with schizophrenia. Psychiatr Genet. 2001;11:79-83.
119. Sakurai K, Toru M, Yamakawa-Kobayashi K, Arinami T. Mutation
analysis of the N-methyl-D-aspartate receptor NR1 subunit gene
(GRIN1) in schizophrenia. Neurosci Lett. 2000;296:168-170.
120. Fan JB, Tang JX, Gu NF, et al. A family-based and case-control
association study of the NOTCH4 gene and schizophrenia. Mol
Psychiatry. 2002;7:100-103.
121. Sklar P, Schwab SG, Williams NM, et al. Association analysis of
NOTCH4 loci in schizophrenia using family and population-based
controls. Nat Genet. 2001;28:126-128.
122. McGinnis RE, Fox H, Yates P, et al. Failure to confirm NOTCH4
association with schizophrenia in a large population-based sample
from Scotland. Nat Genet. 2001;28:128-129.
123. Wei J, Hemmings GP. The NOTCH4 locus is associated with
susceptibility to schizophrenia. Nat Genet. 2000;25:376-377.
124. Miller MJ, Rauer H, Tomita H, et al. Nuclear localization and
dominant-negative suppression by a mutant SKCa3 N-terminal
channel fragment identified in a patient with schizophrenia. J Biol
Chem. 2001;276:27753-27756.
125. Ujike H, Yamamoto A, Tanaka Y, et al. Association study of CAG
repeats in the KCNN3 gene in Japanese patients with schizophrenia, schizoaffective disorder and bipolar disorder. Psychiatry Res.
2001;101:203-207.
126. Feng J, Craddock N, Jones IR, et al. Systematic screening for
mutations in the glycine receptor alpha2 subunit gene (GLRA2) in
patients with schizophrenia and other psychiatric diseases.
Psychiatr Genet. 2001;11:45-48.
127. Freedman R, Adams CE, Adler LE, et al. Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. Am J Med Genet. 2000;97:58-64.
128. Freedman R, Leonard S, Gault JM, et al. Linkage disequilibrium
for schizophrenia at the chromosome 15q13-14 locus of the alpha7nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J
Med Genet. 2001;105:20-22.
129. Wright P, Nimgaonkar VL, Donaldson PT, Murray RM. Schizophrenia and HLA: a review. Schizophr Res. 2001;47:1-12.
130. McMurray CT. DNA secondary structure: a common and causative
factor for expansion in human disease. Proc Natl Acad Sci U S A.
1999;96:1823-1825.
131. Mott FW. The Huxley lecture on hereditary aspects of nervous and
mental diseases. BMJ. 1910;2:1013-1020.
132. Penrose LS. The problem of anticipation in pedigrees of dystrophia
myotonica. Ann Eugenics. 1948;14:125-132.
133. Petronis A, Kennedy JL. Unstable genes—unstable mind? Am J
Psychiatry. 1995;152:164-172.
Mayo Clin Proc, October 2002, Vol 77
134. Johnson JE, Cleary J, Ahsan H, et al. Anticipation in schizophrenia:
biology or bias? Am J Med Genet. 1997;74:275-280.
135. Bassett AS, Honer WG. Evidence for anticipation in schizophrenia.
Am J Hum Genet. 1994;54:864-870.
136. Alda M, Lit W, Ahrens B, et al. Age of onset in sporadic and
familial schizophrenia [abstract]. Schizophr Res. 1994;11:101-102.
137. Gorwood P, Leboyer M, Falissard B, Rouillon F, Jay M, Feingold J.
Further epidemiological evidence for anticipation in schizophrenia.
Biomed Pharmacother. 1997;51:376-380.
138. Penrose LS. Survey of cases of familial mental illness. Eur Arch
Psychiatry Clin Neurosci. 1991;240:315-324.
139. Bassett AS, Husted J. Anticipation or ascertainment bias in schizophrenia? Penrose’s familial mental illness sample. Am J Hum
Genet. 1997;60:630-637.
140. Schalling M, Hudson TJ, Buetow KH, Housman DE. Direct detection of novel expanded trinucleotide repeats in the human genome.
Nat Genet. 1993;4:135-139.
141. Morris AG, Gaitonde E, McKenna PJ, Mollon JD, Hunt DM. CAG
repeat expansions and schizophrenia: association with disease in
females and with early age-at-onset. Hum Mol Genet. 1995;4:19571961.
142. O’Donovan MC, Guy C, Craddock N, et al. Expanded CAG repeats
in schizophrenia and bipolar disorder. Nat Genet. 1995;10:380381.
143. O’Donovan MC, Guy C, Craddock N, et al. Confirmation of association between expanded CAG/CTG repeats and both schizophrenia and bipolar disorder. Psychol Med. 1996;26:1145-1153.
144. Li SH, McInnis MG, Margolis RL, Antonarakis SE, Ross CA.
Novel triplet repeat containing genes in human brain: cloning,
expression, and length polymorphisms. Genomics. 1993;16:572579.
145. Neri C, Albanese V, Lebre AS, et al. Survey of CAG/CTG repeats
in human cDNAs representing new genes: candidates for inherited
neurological disorders. Hum Mol Genet. 1996;5:1001-1009.
146. Albanese V, Holbert S, Saada C, et al. CAG/CTG and CGG/GCC
repeats in human brain reference cDNAs: outcome in searching for
new dynamic mutations. Genomics. 1998;47:414-418.
147. Campuzano V, Montermini L, Molto MD, et al. Friedreich’s ataxia:
autosomal recessive disease caused by an intronic GAA triplet
repeat expansion. Science. 1996;271:1423-1427.
148. Sanpei K, Takano H, Igarashi S, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat
expansion and cloning technique, DIRECT. Nat Genet. 1996;
14:277-284.
149. Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P. Molecular characterization of schizophrenia viewed by microarray
analysis of gene expression in prefrontal cortex. Neuron. 2000;
28:53-67.
150. Smith RE, Haroutunian V, Davis KL, Meador-Woodruff JH. Vesicular glutamate transporter transcript expression in the thalamus
in schizophrenia. Neuroreport. 2001;12:2885-2887.
151. Ibrahim HM, Hogg AJ Jr, Healy DJ, Haroutunian V, Davis KL,
Meador-Woodruff JH. Ionotropic glutamate receptor binding and
subunit mRNA expression in thalamic nuclei in schizophrenia. Am
J Psychiatry. 2000;157:1811-1823.
152. Mimmack ML, Ryan M, Baba H, et al. Gene expression analysis in
schizophrenia: reproducible up-regulation of several members of
the apolipoprotein L family located in a high-susceptibility locus
for schizophrenia on chromosome 22. Proc Natl Acad Sci U S A.
2002;99:4680-4685.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.