FEATURE REVIEW
Schizophrenia genes, gene expression, and
neuropathology: on the matter of their convergence
PJ Harrison
1
and DR Weinberger
2
1
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK;
2
Genes, Cognition and Psychosis Program,
National Institute of Mental Health, NIH, Bethesda, MD, USA
This review critically summarizes the neuropathology and genetics of schizophrenia, the
relationship between them, and speculates on their functional convergence. The morpholo-
gical correlates of schizophrenia are subtle, and range from a slight reduction in brain size to
localized alterations in the morphology and molecular composition of specific neuronal,
synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal
thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity
and of the synapse. Although attractive, such concepts are vague, and differentiating primary
events from epiphenomena has been difficult. A way forward is provided by the recent
identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT,
DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with
what is known of their expression profiles and biological roles in brain and how these may be
altered in schizophrenia. The evidence for several of the genes is now strong. However, for
none, with the likely exception of COMT, has a causative allele or the mechanism by which it
predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may
all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and
the development and stabilization of cortical microcircuitry. NMDA receptor-mediated
glutamate transmission may be especially implicated, though there are also direct and
indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the
putative roles of the genes at the molecular and synaptic levels and the existing understanding
of the disorder at the neural systems level. Characterization of a core molecular pathway and a
‘genetic cytoarchitecture’ would be a profound advance in understanding schizophrenia, and
may have equally significant therapeutic implications.
Molecular Psychiatry (2005) 10, 40–68. doi:10.1038/sj.mp.4001558
Published online 20 July 2004
Keywords:
dopamine; genetics; glutamate; NMDA receptor; psychosis; synaptic plasticity
To the molecular psychiatrist, Alzheimer’s disease
and schizophrenia provide an interesting contrast. In
the former there is, by definition, a diagnostic
neuropathology, which is unequivocal, quantifiable,
and correlates with the clinical severity of the
disorder. Substantial elements of the genetic archi-
tecture are known, with autosomal dominant muta-
tions in several genes, and a major influence of the
apolipoprotein E4 allele on disease susceptibility. A
cardinal neurochemical deficit, in cholinergic trans-
mission, has been identified and characterized. With
this fundamental knowledge in place, significant
strides have been made in its pharmacotherapy,
crucially moving the field forward from therapeutic
nihilism. The discovery that familial Alzheimer’s
disease is caused by mutations in genes which impact
on b-amyloid trafficking and metabolism led to the
advancement of the b-amyloid hypothesis
1
and
thence b-amyloid targeted treatments, which hold
the promise of retarding or reversing the disease.
2
These developments have together revolutionized
geriatric psychiatry and engendered an optimism
which could not have been foreseen a decade ago.
By comparison, the understanding of schizophrenia
remains rudimentary. Neuropathological findings are
controversial and not diagnostically useful; loci and
genes have been difficult to identify and replicate.
Equally, treatment has improved only incrementally.
In the absence of definitive genes or pathogenic
molecular mechanisms, it is not surprising that there
is no equivalent of the secretase inhibitors and
vaccines being developed in Alzheimer’s disease.
However, the situation seems about to change;
indeed, it may be changing already. The purpose of
this review is to provide a critical update on the
neuropathology and genetics of schizophrenia, and to
consider how they may intersect in the pathogenesis
Received 02 April 2004; revised 22 June 2004; accepted 28 June
2004
Correspondence: PJ Harrison, Neurosciences Building, University
Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX,
UK. E-mail: paul.harrison@psych.ox.ac.uk or DR Weinberger,
NIH, 10 Center Drive, Bethesda, MD 20892, USA.
E-mail: weinberd@intra.nimh.nih.gov
Molecular Psychiatry (2005) 10, 40–68
&
2005 Nature Publishing Group All rights reserved 1359-4184/05 $30.00
www.nature.com/mp
of the disorder. Relatively more space is devoted to
the genetics because of dramatic recent develop-
ments. We postulate that the genes predispose, in
various ways but in a convergent fashion, to the
central pathophysiological process: an alteration in
synaptic plasticity, especially affecting NMDA recep-
tor (NMDAR)-mediated glutamatergic transmission,
that disrupts neural microcircuits involved in higher-
order
cortical
function,
particularly
executive
processing.
Neuropathology of schizophrenia: a summary
Macroscopic findings
The cumulative literature, including several meta-
analyses, disproves the null hypothesis that there is
no neuropathology of schizophrenia, at least at the
macroscopic level. Recent reviews should be con-
sulted for details and full citations;
3–8
here, we
summarize the major findings and cite only a
selection of papers.
Along with ventricular enlargement, there are small
but significant reductions in brain volume
9,10
and
weight.
11
Imaging studies particularly implicate the
hippocampus,
12,13
association neocortex (prefrontal
and superior temporal),
4,6,14
and thalamus.
15
There are
also abnormalities reported in a diverse range of other
parameters, including cortical thickness,
16
cortical
gyrification,
17,18
hippocampal shape,
19,20
and cerebral
asymmetry.
21,22
Volumetric differences are seen in
first-episode and drug-naı¨ve patients,
23–25
and some
exist before the onset of psychosis
26
and occur in at
risk and unaffected relatives.
27–29
Thus, there is
evidence of a neuropathology intrinsic to the disease
process, part of which may be related to genetic
predisposition rather than to the illness itself.
30
While the demonstration that schizophrenia is
beyond doubt a brain disease has been of fundamental
importance,
31,32
it is also important not to over- or
misinterpret these data.
33
Firstly, there are incom-
plete, inconsistent, and even contradictory reports for
many findings: for example, concerning the brain
structures most affected and the clinicopathological
correlations;
34–36
also, the question of progression or
variation in the changes during the course of illness
and their seemingly counterintuitive clinical implica-
tions.
37–39
Secondly, the magnitude of change in each
parameter is usually small, and concerns group
means with considerable overlap between schizo-
phrenia and comparison groups. Third, when another
disease group is available for a direct comparison, the
findings are rarely specific. Overall, therefore, schizo-
phrenia cannot be considered to have a clear or
‘diagnostic’ neuropathological signature. This may of
course change in the future as new methods are
applied. On the other hand, it seems more likely that
the macroscopic differences, and the histological
abnormalities to be mentioned below, will prove to
be downstream or tangential manifestations of the
core neurobiological phenotype, viz. the genetically
influenced molecular disruption of neural circuits
subserving particular neurofunctional domains. We
return to this issue later.
Histological findings
An important negative observation is that schizo-
phrenia is not associated with an increased frequency
of Alzheimer’s disease
40–42
nor other recognized
neurodegenerative disorders, nor astrogliosis.
43
This
applies even in schizophrenics with dementia,
41,42
unless there is a coincidental pathology (eg infarc-
tion).
44
These negative findings mean that the cogni-
tive impairments of schizophrenia, increasingly
viewed as core features and therapeutic targets, are
not explained in conventional neuropathological
terms.
45,46
Also, their absence, by default, gives
support to a developmental origin of the neuropathol-
ogy, and constrains theories of schizophrenia as a
progressive disorder, at least in a classical neurode-
generative sense.
38,47
Robust positive findings have been harder to come
by, in part because the studies have been smaller and
fewer, and it remains the case that no single
abnormality can be considered wholly established.
The most intriguing and potentially most notable
histological observations are those of aberrantly
located or clustered neurons, especially in lamina II
of the entorhinal cortex,
48–51
and in the neocortical
white matter,
52–57
since these kinds of abnormality are
strongly indicative of an early neurodevelopmental
anomaly affecting neuronal migration, survival, and
connectivity.
58,59
The number of positive reports
means that these findings cannot be dismissed, and
should be actively considered as candidate neuro-
pathological features of the disorder. However,
neither can they yet be accepted uncritically, as there
are methodological limitations, negative studies, and
the positive studies disagree as to the nature of the
alterations.
57,60–63
There are several other histological findings to note
that lack the strong neurodevelopmental implication
of aberrantly located neurons, but which are reason-
ably well replicated and together may provide clues
about the nature of the disorder and may relate more
directly to its genetic origins. First, the cell bodies of
pyramidal neurons in the hippocampus and neocor-
tex are smaller in many
64–69
though not all
70,71
studies.
Smaller perikarya are probably a correlate of a less
extensive or less active axodendritic tree which the
neuron has to support.
72
Second, consistent with this
interpretation, the same neuron populations have
fewer dendritic spines and reduced dendritic arbor-
izations, as assessed using Golgi stains
73–76
and
molecular markers such as MAP2 and spinophi-
lin,
77,78
though inconsistencies (or anatomical hetero-
geneity) exist here as well.
79,80
There are also
reductions in several presynaptic markers of pyrami-
dal and other neurons, with decreased expression of
genes such as synaptophysin, SNAP-25 and complex-
in II.
81,82
Third, the density of some interneurons,
especially parvalbumin-immunoreactive cells, and
their synaptic projections are reduced.
83,84
Fourth,
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
41
Molecular Psychiatry
though there is no overall change in the number of
neurons in the cerebral cortex
85
or hippocampus,
86,87
the thalamus may have fewer neurons, notably in the
mediodorsal nucleus and pulvinar.
88–93
However, the
mediodorsal findings also exemplify the frustration of
research in this field: despite the five positive
reports,
88–92
two comparable subsequent studies have
been resoundingly negative.
94,95
Fifth, a reduction in
the number and function of oligodendrocytes is
becoming apparent from ultrastructural,
96
morpho-
metric
97,98
and microarray
99,100
studies. Given the role
of oligodendrocytes in myelination and other aspects
of neuronal and synaptic integrity,
97,101,102
their
involvement in schizophrenia is likely to be inextric-
ably linked to the neuronal alterations mentioned,
and to the functional consequences thereof, but at
present it is not clear which are primary changes and
which are secondary. Moreover, oligodendrocytes are
an especially vulnerable cell population to many
insults, and molecular abnormalities of oligodendro-
cytes are reported in association with many CNS
disorders not involving myelin directly. A similar
interpretational query affects another neuropatholo-
gical theme that has emerged recently, that of
mitochondrial and metabolic involvement in schizo-
phrenia, for which there is also morphological,
103
biochemical,
104,105
and molecular
106,107
evidence.
Additional conclusions regarding the post-mortem
data are facilitated by consideration of imaging and
other in vivo findings. For example, smaller neurons
with less extensive (or less active) arborizations may
well explain the reduced N-acetylaspartate (NAA)
signal in schizophrenia, which is used as a marker of
neuronal ‘integrity’ in proton magnetic resonance
spectroscopy studies
108
and which is also decreased
in post-mortem tissue.
109
In tandem with the apparent
decreases in some presynaptic and glial populations,
these morphometric changes could also contribute to
decreased regional brain volumes and cortical thick-
ness, via a reduced neuropil.
110
The fact that
volumetric and NAA deficits are seen in first episode
and medication-free subjects
111,112
is important as it
supports the assumption that the neuropathological
observations—all of which are based on chronic,
medicated patients—are not merely a consequence of
the illness or its treatment. The latter risk is, in any
event, often exaggerated; there is little evidence that
antipsychotics cause the morphometric and molecu-
lar alterations (except within basal ganglia), and often
quite strong evidence that they do not.
113,114
A similar
reassurance applies to autopsy delay effects.
115
In-
stead, relatively neglected factors such as smok-
ing,
116,117
substance
misuse,
118
and
premortem
events,
115,119–121
may be greater confounders.
Synaptic connectivity in schizophrenia
In summary, rather than having a distinctive signa-
ture, the neuropathology of schizophrenia seems to
consist of quantitative alterations in various normal
parameters of neural microcircuitry, ranging from the
dendritic tree to the cell body and axon to the
synaptic terminal, and including associated glial
elements. In this respect, the neuropathology may be
viewed as representing the structural anlage of the
functional ‘dysconnectivity’ which is prominent in
pathophysiological models of the disorder.
3,122–128
A
more focused variant of these models is the concept of
schizophrenia as a disorder of the synapse.
129–131
Another view of altered connectivity emphasizes
more the ‘cabling’ itself, based on the recent evidence
for white matter abnormalities emerging from MRI
and microarray studies.
132,133
Formulations of this kind are inevitably weak and
imprecise, since the nature of the pathology is only
partially known, and since any severe brain disorder
is almost bound to affect, one way or another, most
neuronal, glial, and synaptic populations. Neverthe-
less, there are some intriguing clues. First, with regard
to synaptic pathology, the few electron microscopy
data suggest that it is only partly morphological, in
the sense of a loss or other visible abnormality of
synaptic terminals, the rest being presumably ‘mole-
cular’; that is, affecting the composition, activity, or
plasticity of the synaptic machinery.
81,82
Parentheti-
cally, this continuum of conventional neuropathology
with biochemical and functional indices (eg receptor
densities, growth factor abundance, fMRI signal, etc)
is also seen in Alzheimer’s disease,
134,135
and in
normal synaptic plasticity,
136
and will prove relevant
when we address how the genes may operate. Second,
though the neurochemical phenotype of connections
affected in schizophrenia is unclear, several types are
clearly involved,
137
including glutamatergic ones in
the hippocampus
82,138,139
and cerebellum,
140
and
alterations in some GABAergic as well as glutamater-
gic synaptic populations in dorsolateral prefrontal
cortex (DPFC);
83,141,142
changes in cortical dopaminer-
gic innervation
143
and signalling
79,144
are also appar-
ent. The glutamate data are noteworthy as they add to
the increasing focus on this transmitter and its
interaction with dopamine,
145–151
and will also be
seen to be genetically pertinent. Third, concerning the
timing of the synaptic pathology, there is altered
expression in schizophrenia of several ‘developmen-
tal’ genes such as DLX1,
152
reelin,
153
and semaphorin
3A
154
, and correlations between their expression and
that of other synaptic markers.
57,153
These findings
provide some neuropathological support for a devel-
opmental basis to schizophrenia, perhaps via effects
on synaptogenesis or synaptic pruning; however, they
should not be overinterpreted, since every gene
implicated in schizophrenia probably plays some role
in brain development and, conversely, the very fact
that so-called developmental genes continue to be
expressed in adulthood implies that they have on-
going functions (which may or may not be the same as
those during maturation).
The current gaps in knowledge make a more robust
and fine-grained understanding of the neuropathol-
ogy of schizophrenia desirable, and further efforts to
this end continue in many laboratories, including
ours. However, the subtlety of the pathology, and the
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
42
Molecular Psychiatry
intrinsic conceptual and practical limitations of post-
mortem brain research, mean that this approach is
unlikely to yield a full explanation. Certainly in
isolation it will not explain the cause of the
pathology, which ultimately is the major goal. To do
so requires identification of the susceptibility genes,
since these presumably are pathogenic, at least partly,
via their influence on the formation, maintenance,
and activity of the brain systems that underlie the
disorder. We therefore revisit the neuropathology after
discussion of the leading genetic candidates. First,
however, we consider briefly some of the key issues
which have affected the field of schizophrenia
genetics, and which significantly influence interpre-
tation of the recent data.
The search for schizophrenia genes
Twin studies show unequivocally that schizophrenia
is predominantly a genetic disorder, with estimates of
heritability of risk of around 80%.
155,156
Hence, while
factors other than DNA sequence variation are
important too, identification of the genes responsible
for this high heritability will be critical to under-
standing the disease, and even the environmental and
epigenetic factors may be difficult to unravel without
parsing based on genotype. Family studies show that
simple major gene effects are unlikely; instead,
polygenic models, that is, the effects of multiple risk
genes acting additively or multiplicatively, provide
the best explanatory fit.
157
Thus, like cancer, diabetes,
and heart disease, schizophrenia is a complex genetic
disorder, not characterized by a single causative gene
and not showing simple patterns of inheritance
(though there may be rare examples of such families).
Similarly, its genes will each account for only a small
increment in risk (eg no greater than a three-fold risk
elevation in siblings),
158
are likely to be modified by
other genes, including protective ones, both addi-
tively and epistatically, and also to show environ-
mental modification. The genetic architecture of
susceptibility is almost certainly heterogeneous,
meaning that no particular constellation of genes will
be characteristic of most ill individuals. Furthermore,
the same causative allele(s) may have a variable
phenotype depending on genetic background.
Much of the scepticism about finding genes for
schizophrenia, and indeed the difficulties encoun-
tered by researchers, was fuelled by a failure to
appreciate the implications of the assumptions above,
and there continue to be substantial and unresolved
issues.
159
One concerns the interpretation of the
existing evidence for linkage based upon the 20
genome-wide scans reported to date (references
available on request to DRW). These studies have
together implicated much of the genome, and in only
four studies has any region reached accepted levels of
statistical significance (6p22–24;
160
8p21–22;
161
1q21–
22;
162
and 10q25.3–q26.3
163
). Each of these regions,
however, has been decidedly unremarkable in other
studies. There have been many explanations offered
for these apparent inconsistencies, including lack of
power to detect the weak linkages expected in
complex genetic disorders, and problems related to
sample ascertainment biases, diagnostic imprecision,
and genetic heterogeneity.
Two recent meta-analyses have sought clarification
by combining the results of the genome-wide studies.
Badner and Gershon
164
combined the uncorrected P-
values for markers clustered around a region showing
evidence for linkage in any study (defined as a
nominal pointwise P
o0.01). After correcting for
region size and marker number, but not sample size,
three loci reached genome-wide significance: 8p, 13q,
and 22q. They concluded that these are valid linkage
regions, likely containing one or more susceptibility
genes. Lewis et al
165
applied a within-study rank-
order analysis of published and some unpublished
datasets and produced rather different results. Their
approach is less dependent on models of inheritance
and heterogeneity and even to marker order; instead,
they lumped marker data into 30 cM bins across the
genome (120 bins in all) and ranked each bin within a
study based on the most significant evidence for
linkage of any marker in that bin. The bin rankings
were averaged across all the studies and permutation
tests used to reject the null hypothesis that rank and
relative order for any given bin were random. Under
stringent criteria, genome-wide significance was
found only for 2p12–22.1, a region that had not
achieved even nominal significance in any single
study. Using a more liberal statistical threshold,
several other loci emerged, viz., in decreasing order
of significance, 5q, 3p, 11q, 2q, 1q, 22q, 8p, 6p, 20p,
and 14q. The authors concluded that multiple regions
of the genome were likely to contain genes for
schizophrenia; an optimist would also note that 8p
and 22q were identified in both meta-analyses.
These meta-analytic approaches amplify signals
that appear to generalize across multiple samples
(even if none are particularly impressive in a single
study) and reduce strong signals that are unique to
only a few samples. The ultimate validation of these
results will be the evidence supporting the genes
themselves. It is worth noting, however, that of the
genes identified so far as promising candidates, none
map to 2p and only COMT and neuregulin map to loci
common to both meta-analyses. The well-described
weakness of linkage as a strategy for mapping genes of
small effect
158
raises the possibility that families in
positive linkage studies may be segregating uncom-
mon large effect genes. Alternatively, each of the
positive linkage regions may contain multiple sus-
ceptibility genes that individually account for small
increments in risk across populations (ie odds ratios
o2 for a specific gene), but together account for
linkage across families that are heterogeneous for risk
genes in these regions. Consistent with this latter
scenario is evidence that genes associated with
schizophrenia that do not map to linkage regions
show similar genotypic relative risks as genes that do
(see below).
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
43
Molecular Psychiatry
The inconsistencies and uncertainties regarding the
linkage findings have generated two schools of
thought: a sceptical one, which doubts all results
and views the strategy as nonproductive,
166
and an
optimistic one,
159
which sees the results as being
consistent with predictions of weak effects of multi-
ple genes and with genetic heterogeneity, and which
looks forward to ever larger-scale studies. In our view
this is a stale debate since ultimately validation
comes from the discovery of a gene or genes within
the linkage region. Hence, it is time to move away
from solely statistical arguments to directly test the
importance of specific loci or genes.
167
Armed with
the public genome databases, researchers can now
identify candidate genes or expressed sequences
within the linkage regions and, in tandem with
available functional information, make a case for
gene identification. This has led to testing of specific
allelic variants, usually single-nucleotide polymorph-
isms (SNPs), within or adjacent to a gene. Demonstra-
tion of an increased frequency of an allele in
schizophrenics compared to a suitable comparison
group constitutes evidence of genetic association.
Such association, if not an artefact (eg of multiple
testing, genotype errors, or population stratification),
means that the SNP is either causative or is in linkage
disequilibrium (LD) with a variant that is. Associa-
tion, however, does not mean that the gene has been
found. It may also be that the detected association is
in fact a proxy for a functional variant in a nearby
gene. A precedent for this is lactose intolerance, a
genetic disorder characterized by decreased lactase
expression in the gut. The gene abnormality, however,
is a polymorphism located in another gene that
encodes a regulatory element impacting on lactase
expression.
168
If we knew nothing about the biochem-
istry of lactose intolerance, we might be misled by the
various functions of the other gene. This means that
allelic association per se is not evidence of gene
identification. A further caveat about the association
data is that the risk alleles related to schizophrenia
vary between studies; in other words, though associa-
tion to several genes is well replicated, specific alleles
are not. The implications of this are unclear; while it
has been argued that the inconsistencies reflect
haplotype differences between populations related
to ancestral background,
169,170
this largely post hoc
interpretation will not be confirmed or refuted
until the causative mutations are identified. In any
event, the essential point is that the end game in
identifying susceptibility genes for polygenic disor-
ders like schizophrenia will not come from statistics,
either linkage or association, but will require biologi-
cal evidence that the risk variant impacts on the
pathogenesis of the disease.
167,171
This end game
involves a convergence of analyses at many levels,
including functional studies of gene variation,
animal and cell model systems, and molecular
neuropathology in human brain. Indeed, some of the
post-mortem findings in schizophrenia (eg synaptic
markers) may serve as molecular phenotypes to
validate the pathogenic implications of susceptibility
alleles.
We now consider the genes recently reported to be
associated with schizophrenia, focussing on those
that are positive in at least three published indepen-
dent samples, adopting the criterion for robustness
recommended by Lohmueller et al.
172
Several other
genes are also mentioned which have not yet reached
this arbitrary threshold, recognizing that not all will
stand the test of time. For each gene, the genetic
evidence is considered along with what is known of
its function and expression in the brain, and how it
may be affected in schizophrenia. Table 1 summarizes
the genes to be considered along with our opinion as
to the current strength of the evidence rated in four
domains. We do not cover some earlier genetic
associations (eg HTR2A, DRD2, DRD3), reviewed
elsewhere.
159,173–175
The genetics, expression, and biology of
schizophrenia susceptibility genes
Catechol-O-methyl transferase (COMT)
Catechol-O-methyl transferase (COMT) is the most
plausible of the susceptibility genes a priori, because
of its role in monoamine metabolism, and because the
main genetic variant being associated with schizo-
phrenia is functional. Its candidacy is furthered by its
mapping to 22q11, implicated in both meta-ana-
lyses,
164,165
and hemideletion of this region produces
velocardiofacial syndrome (VCFS), a condition asso-
ciated with manifold increased risk of schizophrenia-
like psychoses.
176
We therefore consider COMT first
and in detail, even though the statistical evidence for
its association with schizophrenia is not as strong as
for some of the other genes.
Identified in 1958,
177
COMT catalyses the methyla-
tion of catechols, such as dopamine, norepinephrine,
and catecholoestrogens.
178,179
COMT exists in mem-
brane-bound (MB) and soluble (S) forms, which differ
by the presence of a 50 amino-acid signal anchor in
MB-COMT. In peripheral tissues and in rodents,
S-COMT predominates, but in human brain it is
MB-COMT.
180
MB-COMT has much greater affinity for
dopamine than S-COMT, but a lower Vmax,
181
suggesting that brain COMT has high efficiency but
low capacity, that is, suited to neurotransmission.
COMT is expressed as two mRNAs, of 1.5 and 1.3 kb,
corresponding to two start codons and two promoter
elements within a 27 kb sequence.
180
The longer
transcript can give rise to MB- and S-COMT, whereas
only S-COMT is produced from the shorter transcript;
the latter is rare in human brain.
180,182,183
Early studies
suggested that COMT, especially S-COMT, was a glial
enzyme, but subsequent analyses show that COMT is
expressed primarily in neurons, and is much more
abundant in prefrontal cortex and hippocampus than
in
striatum
or
in
brainstem
dopamine
neu-
rons,
178,183,184
supporting conclusions from pharma-
cological studies that COMT inactivates catechols at
postsynaptic sites.
185
The distribution, together with
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
44
Molecular Psychiatry
other data,
186,187
implicates COMT in cortical inter-
neuronal monoaminergic signalling, especially dopa-
mine. However, the precise distribution of COMT
remains unclear; for example, whether COMT can
‘see’ synaptic dopamine; whether and where S and
MB forms are differentially expressed, and the role, if
any, of COMT within dopaminergic neurons.
178,188
Similarly, there is still uncertainty about the role of
COMT in metabolism of norepinephrine and other
catechols in brain. These issues may limit the
conclusions that can be drawn regarding the cellular
and molecular basis for the effect of COMT variation
on cortical function and schizophrenia, discussed
below.
In 1978, a trimodal distribution of peripheral
COMT enzyme activity was reported,
189
consistent
with inheritance of two codominant alleles and three
genotypes. Grossman et al
190
identified a SNP in exon
4, a G–A substitution changing valine (val) to
methionine (met) at position 108/158, that accounts
for the observation; the polymorphism is here
denoted as val158met. The amino-acid change im-
pacts on the stability of the enzyme, such that val-
COMT has significantly lower enzyme activity than
met-COMT.
181,191
Both S- and MB-COMT are affected.
Early studies suggested that the alleles account for up
to four-fold variation in enzyme activity,
181,191
but this
was determined at nonphysiological temperatures;
more recent data show closer to a two-fold variation
in activity in human brain
192
and other tissues.
193
Its functionality has led to the val158met poly-
morphism being extensively investigated in schizo-
phrenia, with more than 15 association studies
reported. The results are decidedly mixed. There are
at least eight studies claiming evidence for associa-
tion to the val allele, but as many with negative
results, although only one with association to the met
allele (refs on request to DRW). A recent meta-
analysis was inconclusive, but showed that any effect
would be small (odds ratio 1.2–1.4).
194
The reasons for
the inconsistencies are not straightforward. Most
studies are small and underpowered to reject associa-
tion, since the allele frequency difference between
patients and controls, even in the positive studies, is
only
B5–8%. Moreover, the allele frequency shows a
marked variation between populations,
195,196
and so
occult population structure (ethnic stratification)
could easily obscure small case–control differences,
as could ascertainment biases hidden in incomplete
characterization of controls. To help circumvent these
problems, seven studies have reported transmission
of COMT alleles within families. In five,
197–201
greater
transmission of val158 alleles was found, which
reached nominal significance in four studies,
197,199–201
with a similar odds ratio in the fifth.
198
Although the
data in total show that COMT by itself contributes at
most a very small increase in genetic risk for
schizophrenia, the chances of finding a significant
positive association to val-COMT in eight indepen-
dent samples (four from family studies and four from
case–control studies) is slim, especially given the
prior linkage data and biological plausibility. Thus, it
is likely that the COMT val158met allele is part of the
complex risk architecture of the illness.
One of the early surprises in the COMT literature
was the more frequent association of schizophrenia
Table 1
Schizophrenia susceptibility genes and the strength of evidence in four domains
Gene
a
Locus
Strength of evidence (0 to þ þ þ þ þ ) for
Association with
schizophrenia
b
Linkage to gene
locus
c
Biological
plausibility
d
Altered expression
in schizophrenia
e
COMT
22q11
þ þ þ þ
þ þ þ þ
þ þ þ þ
Yes, þ
DTNBP1
6p22
þ þ þ þ þ
þ þ þ þ
þ þ
Yes, þ þ
NRG1
8p12–21
þ þ þ þ þ
þ þ þ þ
þ þ þ
Yes, þ
RGS4
1q21–22
þ þ þ
þ þ þ
þ þ þ
Yes, þ þ
GRM3
7q21–22
þ þ þ
þ
þ þ þ þ
No, þ þ
DISC1
1q42
þ þ þ
þ þ
þ þ
Not known
G72
13q32–34
þ þ þ
þ þ
þ þ
Not known
DAAO
12q24
þ þ
þ
þ þ þ þ
Not known
PPP3CC
8p21
þ
þ þ þ þ
þ þ þ þ
Yes, þ
CHRNA7
15q13–14
þ
þ þ
þ þ þ
Yes, þ þ þ
PRODH2
22q11
þ
þ þ þ þ
þ þ
No, þ
Akt1
14q22–32
þ
þ
þ þ
Yes, þ þ
The ratings are of course subjective and transient.
a
Gene names, in the order they are discussed in the text.
b
Based on sample sizes and numbers of replications, not the magnitude of the relative risk. þ þ þ ¼ at least three positive
independent studies.
c
Based on the meta-analyses
164,165
and individual studies.
d
Based on information regarding expression and function in vivo or in vitro.
e
Abundance of mRNA or protein, or the relative expression of isoforms or alleles.
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
45
Molecular Psychiatry
with the val not the met allele. Val association has
also been reported in a large population study of
schizophrenia spectrum personality traits.
202
The
classic dopamine hypothesis of schizophrenia would
have predicted the association would be with the low
activity (hence higher dopamine) met-COMT. Egan et
al
200
offered a potential explanation for this apparent
inconsistency and for the mechanism of the val158
association. They found that val-COMT was asso-
ciated with abnormal prefrontal cortical function,
relative to met158, as measured by cognitive tests and
with fMRI activation, even in normal subjects.
Additional evidence of an association of the val158
allele with poorer prefrontal function has emerged
from a number of sources, including several other
studies of cognition,
203–205
fMRI,
206
and EEG.
207
More-
over, performance on comparable tasks in rodents is
improved, together with increased frontal cortex
dopamine release, by COMT inhibition,
187
and COMT
knockout mice reportedly have enhanced memory
(see Weinberger et al,
208
). The implication that COMT
impacts critically on dopaminergic transmission and
associated functions in the prefrontal cortex is
consistent with the anatomical and pharmacological
data mentioned; moreover, COMT knockout mice
show gene dose-dependent increases in dopamine
186
and dopamine turnover
209
in prefrontal cortex com-
pared with striatum; larger cortical than striatal
effects are also seen in studies using COMT inhibi-
tors. The anatomical selectivity can be explained by
the fact that dopamine transporters, which play the
principal role in inactivating synaptic dopamine in
the striatum, are at very low abundance in the
prefrontal cortex,
210,211
and play virtually no role in
cortical dopamine inactivation.
212
The absence of
dopamine transporters gives COMT (and norepi-
nephrine transporters
213
), and the variation in COMT
activity associated with the val158met genotype,
particular impact on cortical dopamine signalling. It
is interesting to note that in dialysis studies of COMT
inhibition
187
and in studies of COMT knockout
mice,
208
changes in norepinephrine levels were not
seen, suggesting that COMT is less important for
norepinephrine flux, perhaps because of the role of
norepinephrine transporters in prefrontal cortex. In
the context of the dopamine hypothesis of schizo-
phrenia, therefore, COMT appears especially relevant
to the cortical deficits and their putative basis in
dopamine hypofunction. Certainly, the range of
prefrontal abnormalities associated with the val allele
(eg poorer executive cognition, cortical processing
inefficiency, and an abnormal P300 evoked EEG
response), are all found more commonly in schizo-
phrenia and in their first-degree relatives, suggesting
that the effect of val-COMT is qualitatively iso-
morphic with the pattern of prefrontal deficits that
characterize the risk biology of the disease.
208
In
passing, it is worth pointing out that if variation in
COMT is linked more strongly with cognitive inter-
mediate phenotypes rather than with the schizophre-
nia syndrome itself, it may partially explain the
inconsistent results of the genetic association studies
based on standard diagnostic criteria.
Although the emphasis has been on the frontal
cortex, COMT genotype may also have influences
elsewhere. For example, there has been considerable
interest in the possibility that abnormal prefrontal
cortical function in schizophrenia (particularly re-
duced cortical DA), could have downstream implica-
tions
for
regulation
of
brainstem
DA
activity
(specifically, increased activity).
122
Akil et al
214
measured tyrosine hydroxylase mRNA in brainstem
dopamine neurons of brains from 23 normal subjects,
using its abundance as a reflection of cortical
excitatory drive on the dopamine neurons. The brain
specimens were genotyped for the val158met poly-
morphism. Consistent with predictions from the
animal literature,
208
val-COMT was associated with
higher tyrosine hydroxylase expression, especially in
neurons projecting to the striatum and amygdala. The
val158 allele may, therefore, not only bias directly
towards diminished prefrontal function, but also
indirectly to disinhibited mesencephalic dopamine
activity. COMT may therefore contribute, along with
other mechanisms,
122,151,215–218
to both cortical dopa-
mine deficiency and mesolimbic hyperdopaminergia
in schizophrenia.
Most COMT association studies have focused on
the val158met polymorphism because of its known
biochemical correlate and the increasing evidence for
its effects on brain function. However, other genetic
variants may also be relevant. Shifman et al
219
reported that two common SNPs, one upstream and
the other in or near the 3
0
untranslated region (3
0
-
UTR), were associated with schizophrenia in a large
sample of Israelis of Ashkenazi descent. They claimed
that the effect of these SNPs was much greater than
that of val158met, though, in fact, the odds ratios did
not differ significantly between the three polymorph-
isms. Moreover, haplotypes containing either or both
risk alleles in combination with val158 were highly
significantly associated with schizophrenia in this
population (P ¼ 9.5 10
8
), more so in women than
men (see below). This level of significance reflects the
large sample sizes (43000), as the odds ratios for the
SNPs and haplotypes were all
B1.3–1.6. Although
the increase in risk from this haplotype was small, its
high frequency in the population translates into a
high attributable risk; it was estimated that 32.5% of
their female schizophrenic population would not be
ill had they not inherited this haplotype.
219
However,
the findings have yet to be replicated, and one
study
201
and two unpublished ones find no enhanced
risk of these other SNPs or haplotypes (see Owen
et al
159
and BS Kolachana, KE Straub, MF Egan and
DR Weinberger, unpublished). Furthermore, no func-
tionality of these SNPs was found in terms of gene or
protein expression or enzyme activity, as measured in
DPFC of over 100 subjects (G Chen, B Lipska,
J Kleinman, DR Weinberger, unpublished). Never-
theless, the observations of Shifman et al
219
together
with other considerations discussed below,
196,220
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
46
Molecular Psychiatry
suggest that the val158met allele alone may not
capture the complexity of the genetic regulation of
COMT activity. It is conceivable that the inconsisten-
cies in the association of val-COMT with schizophre-
nia, and with prefrontal performance, will be clarified
by a more detailed analysis of combinations of
functionally interacting alleles. For example, the
val158 effect may only increase risk of the disease
in individuals who carry other COMT alleles that
exaggerate its biological effect, or who carry modify-
ing alleles in other genes impacting upon dopamine
signalling.
It is unclear whether the effects of COMT genetic
variation on schizophrenia and prefrontal function
are confounded (enhanced or reduced) by differential
allelic expression. Two studies have found no
evidence that val158met impacts upon level of COMT
mRNA.
221,222
These negative findings apply both to
subjects with schizophrenia and controls. However,
Bray et al
220
found that COMT SNPs, including
val158met and two SNPs from the Shifman et al,
219
study did alter expression in human brain homo-
genates, with the high-risk alleles being associated
with
B20% less COMT mRNA. The relatively higher
expression of met-COMT, if also present in terms of
translated protein, would tend to counterbalance the
greater activity of val-COMT. These results, however,
are contradicted by evidence that met-COMT protein
was associated with reduced immunoreactivity in
transfected cell lines and in liver biopsies compared
with val-COMT.
193
These apparently inconsistent
results are yet to be reconciled; in any event, enzyme
activity is ultimately the critical COMT parameter,
and other measures (such as mRNA or protein level)
should be interpreted with caution. The evidence to
date indicates that only the val158met variant has a
clear effect on enzyme activity.
Another potential complicating factor in COMT
studies is gender. There is evidence that COMT shows
stronger association with schizophrenia in females,
219
a more abnormal phenotype in female COMT knock-
out mice,
186
and
B30% lower peripheral COMT
activity in women.
178,179
The basis of the gender
differences may reside in transcriptional regulation
via estrogen response elements in the promoter.
196,223
However, whether COMT expression is sexually
dimorphic is unclear, and there is no indication that
the influence of val158met on prefrontal function
differs between men and women. The role of COMT
in metabolizing catecholoestrogens, and the associa-
tion of the met158 allele with cancer risk in women,
may also be relevant to the gender differences.
179
COMT expression in schizophrenia has been stu-
died in DPFC, and shows only minor alterations.
COMT mRNA
221,222
and protein (E Tunbridge and PJ
Harrison, unpublished) abundance are unchanged,
consistent with earlier negative enzyme activity
data.
224
However, the mRNA distribution may be
altered, with relatively greater expression in the deep
than superficial laminae compared to controls.
221
The
importance of this finding is unknown.
Dysbindin (DTNBP1)
Straub et al
225
reported that variation in dysbindin
(DTNBP1), a conserved 140 kb gene, was associated
with schizophrenia in the Irish families that had
shown linkage to 6p24–22.
160
They identified and
genotyped 17 SNPs, mostly intronic, in a 670 kb
region flanked by two microsatellite markers that
capped one of their two 6p linkage peaks. Several of
the SNPs showed association to schizophrenia, both
narrow and broad diagnoses, in a transmission
disequilibrium analysis of 270 families (consisting
of only 60 fully typed trios). A three-marker haplotype
showed highly significant association to a broad
region of the gene (from introns 2 to 7), with no
significant association to SNPs outside the gene. A
further analysis of the same sample narrowed the
high-risk haplotype block to a 30 kb segment from
within introns 2–5.
226
In both analyses, the high-risk
haplotype was rare, present in less than 7% of the
sample. This means that if this haplotype contains the
causative mutation in this population, and even if it is
highly penetrant, it accounts for a very small
percentage of cases.
Associations between dysbindin and schizophrenia
have subsequently been reported in a number of
studies. Schwab et al
170
studied 203 families from
Germany, Hungary, and Israel (including 150 trios),
some of whom had previously shown linkage to 6p,
and found association to several of the SNPs
identified by Straub et al, and to a six-marker
haplotype block spanning introns 2–5. However, the
alleles associated with schizophrenia were the com-
mon variants, that is, the opposite result to the
association with the rare alleles seen in the Irish
sample. This is not easily explained by ethnic
diversity as the origins of these populations (except-
ing perhaps the Israelis) are not distinct; the authors
suggested that the Irish mutation may have emerged
independently on a more recent ancestral back-
ground. Further complexities have emerged from
other case–control studies. Three samples from
England and Ireland were all negative for the original
SNPs, but showed association to different SNPs,
implicating potentially different functional elements
within the gene.
227,228
Another positive report has
come from a Han Chinese family-based sample, typed
for seven SNPs spanning the Straub et al
225
panel
from introns 1 to 9, and reporting significant over-
transmission of a common five marker haplotype.
229
Again, the original three marker haplotypes positive
in the Irish study were not overtransmitted in this
sample, and the authors did not report their indivi-
dual SNP analyses. Van den Bogaert et al
230
typed four
of the most positive SNPs from the earlier studies,
spanning introns 3 and 4, and an additional marker
contained within the high-risk haplotypes, and
examined three case–control samples, from Germany
(418 cases, 285 controls), Poland (294, 113), and
Sweden (142, 272). These had to be studied separately
because variable allele frequencies were found be-
tween the control groups, starkly illustrating the
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
47
Molecular Psychiatry
potential for stratification errors even in studies of
European populations. The German and Polish
samples proved negative, but one SNP in the Swedes
showed the rare allele slightly enriched in the
patients, and the five marker haplotype was also
positive. When only the cases with a positive family
history were analysed, the associations were stronger,
and the five marker haplotype showed a six-fold
increased risk effect (3% frequency in controls, 18%
in patients). Again, however, the allelic composition
of this haplotype was distinct from earlier reports.
The authors argued that dysbindin may be associated
with familial schizophrenia in particular, although
this was not the case in the other studies. Further
evidence for dysbindin as a susceptibility gene for
schizophrenia has come from a large study of
Bulgarian parent–proband trios, which found highly
significant association with the common alleles of
two SNPs from the original
225
study, as well as with
several undertransmitted 2-, 3-, and 4-marker haplo-
types; however, the haplotypes and individual SNP
alleles were not consisent.
231
Finally, in the Weinber-
ger lab at NIMH, associations with dysbindin have
been found in two datasets. In
B200 American-
Caucasian family trios, a SNP in intron 4 showed
strong association, with overtransmission of the
common allele and multimarker haplotypes contain-
ing this allele, which is also contained within the risk
haplotype seen in the Irish and German samples (RE
Straub, MF Egan and DR Weinberger, unpublished).
In a second family sample of ethnically heteroge-
neous individuals from the NIMH Genetics Initiative
(NIMHGI) dataset, association was found for this SNP
and for several others, but the overtransmitted alleles
were not the same. Notably, several SNPs were
associated with intermediate cognitive phenotypes
related to genetic risk for schizophrenia, especially IQ
and also working and episodic memory;
232
also, a
‘protective’ dysbindin haplotype has been associated
with higher educational attainment.
228
This suggests
that, as with COMT and some of the other genes to be
discussed, variation in dysbindin may prove to be
related to cognitive aspects of schizophrenia as well
as (or more so than) to the core syndrome itself.
In summary, there is considerable evidence that
genetic variation in dysbindin is associated with
schizophrenia, but striking inconsistency in the high-
risk alleles and haplotypes across various popula-
tions, even those of similar geography and ancestry.
This conundrum is unlikely to be resolved until
causative mutations are identified. None have yet
emerged despite extensive resequencing.
228,233
The
evidence so far suggests that there may be true allelic
heterogeneity, that is, a number of mutations have
emerged independently that have caused subtle but
common pathophysiological effects on dysbindin
function. There are many precedents for this; in
cystic fibrosis, for example, over 100 causative
mutations in the same gene have been identified.
Dysbindin is a
B50 kDa protein originally cloned
from a yeast two-hybrid screen of binding partners of
a
- and b-dystrobrevin (to wit, dystrobrevin binding
protein), which are components of the dystrophin-
associated protein complex (DPC) in the neuromus-
cular junction and brain, respectively.
234
Dystrophin
mutations cause several forms of X-linked muscular
dystrophy. In this context, the associations between
dysbindin SNPs and cognitive domains in schizo-
phrenia are noteworthy, as cognitive deficits are
classical features of Duchenne’s muscular dystrophy;
interestingly, this disease also has a neuropathology
reminiscent of schizophrenia, with a fronto-temporal
distribution, cortical heterotopias, and reduced den-
dritic arborization of pyramidal neurons.
235
Since the
DPC is concentrated at the postsynaptic density
(PSD),
236
dysbindin is thought be involved in one or
more PSD functions, which include trafficking and
tethering of receptors (including NMDA, nicotinic,
and GABA
A
receptors) and signal transduction pro-
teins.
237,238
However, a substantial fraction of dysbin-
din occurs presynaptically.
234,239
As the DPC is absent
from this compartment, presynaptic dysbindin may
well associate with different proteins and play
different roles. Dysbindin has a widespread distribu-
tion in the brain, being expressed by many neuron
populations, including pyramidal neurons in the
hippocampus and DPFC, and also in substantia nigra
and striatum.
80,225,234,239
Dysbindin expression is decreased in schizophre-
nia. In DPFC, this has been shown both for protein
240
and mRNA.
80
The latter study also found that one of
the dysbindin SNPs was associated with less mRNA
expression; this observation may be related to the
finding that dysbindin alleles are differentially
expressed in heterozygotes,
241
suggesting that cis-
acting regulatory elements, including possibly the
intronic variants associated with schizophrenia,
could represent a mechanism for the association.
Dysbindin immunoreactivity also has been reported
to be reduced in the hippocampus in schizophrenia,
with the decrease occurring presynaptically.
239
More-
over, the affected pathways were excitatory, and so
this study raises the possibility that dysbindin might
contribute to the hippocampal glutamatergic synaptic
pathology of schizophrenia mentioned above.
242
In-
deed, preliminary evidence suggests that overexpres-
sion of dysbindin increases glutamate release by
pyramidal neurons in culture, possibly because of a
role in vesicular trafficking
243
Finally, it is important
to note that existing anatomical and schizophrenia
data are based on ‘pan’-dysbindin mRNA probes and
antibodies which overlook the possibility that dys-
bindin isoforms may be differentially expressed in the
brain, or differentially altered in schizophrenia.
Neuregulin 1 (NRG1)
In an important paper consisting of linkage, associa-
tion, and animal modelling, Stefansson et al
244
reported evidence that NRG1 is a susceptibility gene
for schizophrenia. Starting with a small sample of 33
families and 105 affected subjects in Iceland, they
performed a microsatellite-based whole genome scan
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
48
Molecular Psychiatry
and found suggestive linkage at 8p12–21, near the 8p
region highlighted in prior scans.
164,165
Using high-
resolution genetic and physical mapping techniques,
they focused on a 5 cM region around their best
marker and identified two large risk haplotypes, one
of which was found in seven families and the other in
two (of the 33 linkage families). The region shared by
the nine families defined a DNA block of 600 kb,
which contained the 5
0
domain of the NRG1 gene.
This region and the entire NRG1 gene was further
explored, using molecular and informatics strategies
and extensive resequencing to uncover 1200 SNPs,
including 15 that are nonsynonymous. Genotyping of
58 of these SNPs in 478 patients and 394 controls (and
121 SNPs in a subsample) revealed a seven-marker
core haplotype spanning a 290 kb block that was
highly significantly associated with schizophrenia
(P
o6.7 10
6
). The core haplotype extended from the
first intron of NRG1 to far upstream of the transcrip-
tion start codon, but included the first exon of the
full-length transcript. Despite the statistical signifi-
cance, the core haplotype was relatively uncommon,
found in approximately 7.5% of controls and 15% of
their patients. Thus, it accounted for a small (
B10%)
incremental risk across the Icelandic population, and
probably does not account entirely for the 8p linkage
signal in the population. Interestingly, none of the
individual SNPs were associated with schizophrenia
nearly as significantly as the haplotype, suggesting
that none of the identified variants are functional
polymorphisms. It is assumed that the risk haplotype
is tagging an ancestral block of DNA that carries the
schizophrenia risk allele(s) accounting for the asso-
ciation. The authors stated that they are resequencing
the full 290 kb region in search of causative alleles
but, as yet, none have been reported.
Because association does not establish causation,
and because the risk haplotype was largely upstream
of the coding sequence, the sequence variation
associated with schizophrenia could be involved in
the action of another gene (c.f. lactase deficiency,
above). Hence, the authors also studied transgenic
mice to see whether disruption of NRG1 mimics
phenomena associated with schizophrenia.
244
NRG1
knockout mice are nonviable, but NRG1
þ /
hetero-
zygotes expressing 50% of normal overall levels of
NRG1 were created by inserting a stop-codon in the
trans-membrane domain (exon 11). The mice devel-
oped normally but were hyperactive when exposed to
novel environments, and were abnormal in the
prepulse inhibition of startle paradigm (PPI). Cloza-
pine ameliorated the hyperactivity but not the PPI
deficit. There was also a small reduction in whole
brain NMDAR binding sites. Similar but less severe
abnormalities were observed in mice heterozygous for
a knockout of ErbB4, a receptor mediating postsynap-
tic effects of NRG1. These findings, together with
those in another hypomorph mouse
245
provide some
support for the plausibility of NRG1 as a schizo-
phrenia gene. However, it is interesting to note a
potential inconsistency between the genetic findings
and the mouse model: the core risk haplotype
implicates NRG1 type II (see below), which is the
only isoform not disrupted by the trans-membrane
domain construct used to create the animal model.
Following the original report, evidence of associa-
tion between NRG1 and schizophrenia has emerged
in multiple populations. Using the same SNPs,
Stefansson et al
246
genotyped 609 patients and 618
controls from Scotland and found an increased
frequency in schizophrenia of the same haplotype
(P ¼ 0.0003, one-tailed), and with a similar relative
risk to that of the Icelandic sample. Several of the
individual SNPs were also significantly more fre-
quent in patients, but with a lesser relative risk than
the haplotype. Three markers within the Icelandic
core haplotype were also typed in 709 unrelated cases
and 710 blood bank controls from England and
Ireland.
247
These data are much less compelling, but
still suggestive; each individual marker was decid-
edly negative (all P40.75) but the three marker
haplotype showed weak association with schizophre-
nia (P
o0.04, one-tailed). When only the 141 subjects
with an affected first-degree relative were included,
the frequency of the high-risk haplotype was en-
hanced from 9.5% in the whole sample to 11.6%
(compared with 7.5% in controls; P
o0.02, one-
tailed)—somewhat akin to the dysbindin association
in the Swedish sample mentioned. However, after this
parsing procedure, the nonfamilial sample, which
presumably is similar to the Scottish singleton
sample
246
, was not associated with the NRG1 haplo-
type. Yang et al
248
conducted a family-based associa-
tion analysis of 248 Han Chinese trios, typing only
three SNPs, viz. the most significant single Icelandic
SNP in the 5
0
upstream sequence, a nonsynonymous
SNP in the second exon, and a SNP in the 5th intron.
They found 50% overtransmission (P
o0.005) of the
same allele that was positive in Stefansson et al,
244
and association at both other SNPs. Although these
SNPs span over a million bases and are not clearly in
LD, these investigators also showed strong association
to several fairly common computational haplotypes
made up of these three markers. In a separate Chinese
sample of 540 patients and 279 controls from
Shanghai, Tang et al
249
typed 13 microsatellites
spanning a 540 kb region around the 5
0
end of
NRG1. They found evidence for association with
individual markers and with four and five marker
haplotypes in the region of the Icelandic core
haplotype, though different alleles were associated
with increased risk in this sample. Another study,
from Ireland, found association of several NRG1
markers to schizophrenia in 243 cases compared to
222 controls.
250
The strongest association was to a
haplotype within intron 1 which overlapped with,
but was not identical to, that found by Stefansson et
al
244,246
A further Chinese study reports strong
association
with
another
closely
overlapping
haplotype, though with a different set of SNPs, in
both a family sample (184 trios, 138 sib pairs) and a
case–control
population
of
298
patients
and
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
49
Molecular Psychiatry
336 controls.
251
The most recent report also shows
association with 5
0
SNPs in NRG1 in Han Chinese
(369 patients, 299 controls, and 352 family trios).
252
These results, notwithstanding two negative stu-
dies,
253,254
argue convincingly that NRG1 is a likely
susceptibility gene for schizophrenia. The associa-
tions are clustered in two regions, one in the 5
0
regulatory domain of the gene, and one further
downstream. The pattern suggests that NRG1, like
dysbindin, manifests allelic heterogeneity with re-
spect to risk for schizophrenia. The occurrence of
multiple risk haplotypes, spanning distant functional
elements of the gene, enhances the likelihood that
NRG1 is the gene, and not a coincidental neighbour.
However, Corvin et al
250
noted that the variants
associated with schizophrenia in their study occurred
close to an expressed sequence tag (EST) cluster
located within the large first intron. The function of
the EST is unknown, but it is possible that variation
in this expressed fragment, or in a cryptic exon, might
contribute to the associations at the NRG1 locus.
How might variation in NRG1 impact on suscept-
ibility for schizophrenia, and how can definitive
evidence for its involvement be produced? As with
the other genes, substantial additional information
beyond statistical association is needed, including
identification of functional sequence variants, knowl-
edge of the normal expression and roles of the many
NRG1 isoforms in the brain and, critically, demon-
stration of what is actually different about the biology
of NRG1 in schizophrenia. Regarding expression,
NRG1 mRNA and protein is detected in neurons of
many areas of developing and adult human brain,
including hippocampus, cerebellum, neocortex, and
some subcortical nuclei, with immunoreactivity ob-
served in cell bodies, dendrites, and axonal projec-
tions,
depending
on
the
neuron
population
concerned.
255
In rat, the various NRG1 isoforms,
discussed below, show differing cellular and regional
expression profiles, highlighting how complex will be
its full characterization in human brain.
256
One study
of NRG1 expression in schizophrenia has been
reported, using real-time PCR to quantify the three
major NRG1 mRNA isoforms in DPFC.
257
It found a
small increase in the type I isoform, and weak
evidence of a change in the relative abundance of
the isoforms; neither finding was related to subjects’
genotype at the two SNPs most strongly associated
with schizophrenia in the original study.
244
There is
preliminary evidence confirming upregulation of type
I NRG1, in another brain series (A Law, B Lipska, CS
Weickert, PJ Harrison, DR Weinberger and J Klein-
man, unpublished), and more extensive studies of
NRG1 expression in schizophrenia and its relation-
ship to genotype are underway.
Regarding what is known about NRG1 function, a
large literature has emerged over the past decade,
showing its involvement in remarkably diverse
aspects of developmental biology, both in the brain
and peripherally. A seminal review should be
consulted for details.
258
NRG1 is a member of the
neuregulin family, comprising NRG1-4, identified in
1992 from a search for proteins that interacted with
cell cycle signalling pathways. NRG1 is a huge gene
(1.4 MB) and is really a family in itself, giving rise to
at least 15 distinct peptides, derived from three
principal isoforms, types I, II, III; a type IV has
recently been reported too.
259
The gene contains
multiple regulatory elements and promoter se-
quences, and the isoforms reflect differing transcrip-
tion initiation sites and alternative splicing. (A range
of other names for NRG1 isoforms exist but are no
longer useful; for example, the type II isoform was
also called glial growth factor, which is misleading as
glial differentiation is primarily subserved by type
III.) All NRG1 isoforms contain an epidermal growth
factor (EGF)-like motif that is critical for cell–cell
signalling, and most are trans-membrane proteins. In
the best-described mode of NRG1 signalling, proteo-
lytic cleavage of NRG1 releases the N-terminal part
including the EGF domain, which interacts with a
membrane-associated ErbB-type tyrosine kinase re-
ceptor on the recipient cell—for example, postsynap-
tic
neuron
or
glial
cell.
NRG1-ErbB
receptor
interaction leads to receptor dimerization, tyrosine
phosphorylation and activation of downstream sig-
nalling pathways.
260,261
Many other modes of NRG1
signalling may also occur. For example, type III NRG1
can interact with postsynaptic ErbB receptors, while
still tethered to the presynaptic membrane, and in
addition to forward signalling, cleavage of the type III
intracellular domain sends retrograde signals to the
nucleus and regulates gene expression within the
NRG1-expressing cell.
262
The large number of NRG1
signalling mechanisms and isoforms parallel the
range of its functional effects.
258,260,263–266
These
include neuronal and glial functions implicated in
schizophrenia, ranging from development (eg neuro-
nal migration, axon guidance, synaptogenesis, glial
differentiation, myelination), to neurotransmission
and synaptic plasticity (eg recruitment of nicotinic,
GABA, and NMDA receptors, long-term potentiation).
It is a reasonable if vague working hypothesis that the
genetic risk for schizophrenia associated with NRG1
is mediated by a molecular ‘bottleneck’ in NRG1
signalling that alters, probably to a small degree and
in a temporally, spatially, and isoform-limited fash-
ion, the efficiency of NRG1 effects on neural devel-
opment and plasticity. It is impossible at this stage to
predict which of the specific NRG1 functions within
these broad domains is most relevant to its involve-
ment in schizophrenia.
Regulator of G-protein signalling 4 (RGS4)
Mirnics et al
267
compared gene expression profiles
from DPFC in brains from five schizophrenia-control
pairs. RGS4 was the only transcript consistently
reduced, out of 7800 sampled. They expanded the
sample to include five more pairs and performed in
situ hybridization in DPFC, and in visual and motor
cortices. In all locations, nine of the 10 patients had
reduced expression of RGS4 mRNA. Noting that RGS4
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
50
Molecular Psychiatry
maps to 1q21–22, the locus with the strongest single
study whole genome linkage finding,
162
Chowdari
et al
268
typed 13 SNPs across a 300 kb segment
spanning the gene in three independent trio-type
datasets: one from Pittsburgh (93 Caucasian trios),
another from New Delhi (269 trios) and the third from
the NIMHGI (39 full trios). Subpopulations of sib-
pairs were also analysed in these samples for allele
sharing. Despite the relatively small sample sizes,
weak evidence for association to RGS4 was found in
each of the populations, though not in an allele-
consistent manner, and reaching significance for
individual SNPs only in the NIMHGHI sample. In
general, association was present for a haplotype block
stretching from intron 1 to approximately 9 kb up-
stream of the transcription start site. However, in the
two American samples, the significant alleles and
haplotypes differed, and there was no significant
association in the Indian sample, just a trend for one
of the NIMHGI haplotypes. The Cardiff group have
reported modest association to two of the RGS4 SNPs
in their dataset of 709 cases and 710 controls,
269
as did
Morris et al
270
in 196 subjects with schizophrenia and
231 controls.
Overall, the genetic data for RGS4 are suggestive,
but it is unclear whether the positive results seen
with linkage, association, and expression represent a
convergence that greatly strengthens the candidacy of
RGS4 as a susceptibility gene, or whether they are at
least partly coincidental. For example, the positive
genetic association to RGS4, which carries a low
relative risk of schizophrenia, is unlikely to relate
directly to the reduction in RGS4 mRNA, which was
seen in nine out of 10 subjects.
267
RGS4 expression is
decreased in Alzheimer’s disease, which is not
associated with the gene,
271
illustrating that the two
findings are not necessarily linked. Also, no potential
coding SNPs have been found in a resequenced
sample or in cases from the expression series,
268
leaving the SNPs without obvious functional corre-
lates. On the other hand, RGS4 certainly has some
biological plausibility as a schizophrenia gene. It is
the most brain-enriched of the 19 human RGS
transcripts,
272
and is abundant in the cerebral cortex,
with much lower levels in thalamus and basal
ganglia.
273
RGS4 is a GTPase activator which desensi-
tizes Gi/o and Gq and so negatively modulates G
protein-mediated signalling via some dopamine,
metabotropic
glutamate,
and
muscarinic
recep-
tors.
274,275
RGS4 is involved in neuronal differentia-
tion
276
and is under dopaminergic regulation.
277
Disrupted-in-schizophrenia 1 (DISC1)
St Clair et al
278
described a large Scottish family in
which a balanced translocation involving chromo-
somes 1 and 11 (1;11)(q42.1;q14.3) was strongly
linked to psychopathology including schizophrenia,
depression, and mania. The 1q breakpoint was cloned
and found to involve two genes, called DISC1 and
DISC2; the latter did not encode a protein, but may be
an inhibitory RNA regulator of DISC1.
279
Evidence for
linkage of schizophrenia to 1q42 has been reported in
three samples.
280–282
In the Finnish samples,
280,282
the
marker with the highest LOD score mapped to DISC1.
Moreover, in the original Scottish kindreds, translo-
cation carriers (ie cytogenetically abnormal but with-
out a psychiatric phenotype) have a reduced P300
amplitude,
283
a physiological EEG trait manifested by
patients with schizophrenia. In another report, a
microsatellite marker near DISC1 was associated with
impaired spatial working memory.
284
These various
pieces of circumstantial evidence support a possible
role for DISC1 in susceptibility to schizophrenia, but
chromosomal rearrangements can disrupt large re-
gions, and the linkage and cognitive associations may
be reflecting variation in another gene on 1q.
Direct evidence relating DISC1 to schizophrenia has
come from two out of three studies. The negative
study found no association with four DISC1 SNPs in a
Scottish population of 267–328 schizophrenics and
426–726 unrelated controls.
285
Hennah et al
286
per-
formed a family-based association study of 28 SNPs in
450 Finnish families and found a three marker
haplotype spanning intron 1 to exon 2 that was
significantly undertransmitted to female probands.
They identified two other significant haplotypes as
well, but could not exclude linkage as the basis of the
finding because association was no longer significant
when the families from the previous positive linkage
analysis were excluded. Interestingly, one of the
undertransmitted haplotypes is in another 1q42 gene,
TRAX, which may coalesce with DISC1 by intergenic
splicing and be expressed as a fusion protein under
certain conditions.
280,287
The third haplotype, which
was the only overtransmitted one, spanned a 10 kb
region including exon 9. This region is near the
chromosomal breakpoint in the Scottish translocation
families. However, this finding also was not signifi-
cant in the nonlinked Finnish families. The associa-
tion with an undertransmitted haplotype is difficult
to interpret, and might suggest that not inheriting
certain haplotypes is in some way protective against
schizophrenia. In the third DISC1 study, Callicott et
al
288
typed 12 SNPs spanning the gene, including
several from the earlier studies, in the Weinberger lab
Caucasian ‘quad’ dataset (260 families containing
index cases, usually one unaffected sib, and parents)
and in an NIMHGI-derived family dataset (67 Cauca-
sian and 51 African-American families). They found
association (P
o0.005) to a coding SNP in exon 11
(cys704ser) that had been negative in both earlier
studies. A three-marker haplotype from intron 8 to
exon 10, including the overtransmitted ser704 allele,
was also positive (P ¼ 0.005 global, P
o0.002 specific).
A trend (P ¼ 0.06) for overtransmission of the same
haplotype was found in the Caucasian NIMHGI
sample, and significant association to a SNP in intron
3 was also found in the African Americans. These
investigators also found relationships between the
cys704ser polymorphism and intermediate pheno-
types related to schizophrenia, with the ser704 allele
being associated with reduced hippocampal grey
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
51
Molecular Psychiatry
matter volume and NAA signal, and abnormal
engagement of the hippocampus during several
cognitive tasks as assayed with fMRI. These conver-
gent data implicate DISC1 in genetic risk for schizo-
phrenia and suggest that the mechanism may involve
hippocampal development and function; as such they
also illustrate how genes may implicate the various
parameters of neuropathology outlined above. How-
ever, the evidence for DISC1 association with schizo-
phrenia is not yet conclusive, and the causative
variant(s) await identification.
DISC1 is a complex gene with protean but poorly
understood implications for development and plasti-
city. The gene has 13 exons spanning over 200 kb, and
encodes a protein of 854 amino acids. It is associated
with numerous cytoskeletal proteins involved in
centrosomal and microtubule function, and with cell
migration, neurite outgrowth, and membrane traffick-
ing of receptors and possibly mitochondrial func-
tion.
289–293
Different domains of DISC1 interact with
distinct families of proteins involved in these various
functions, so allelic heterogeneity could impact
differentially on DISC1 function. For example, re-
gions of the gene downstream from the translocation
breakpoint, including exon 10, are critical for DISC1
binding to neurite outgrowth factors (eg NUDEL and
FEZ1) and transcription factors (eg ATF4/CREB2),
and for the normal intracellular distribution of
DISC1.
291
DISC1 mRNA expression is highest prena-
tally, at least in the mouse,
292
and there is a splice
variant expressed during human fetal development
which alters exon 10.
279
Consistent with its potential
influence on hippocampal structure and function,
284
DISC1 expression is prominent in limbic struc-
tures.
294,295
The distribution of DISC1 between cell
types and compartments has not been described in
detail, but is said to be localized in mitochondria, as
well as in cytoplasm, nuclei, neurites, and the plasma
membrane.
289
DISC1 expression in schizophrenia has
not yet been reported.
Metabotropic glutamate receptor-3 (GRM3; mGluR3)
After dopamine, glutamate is arguably the neuro-
transmitter system most implicated in schizophre-
nia,
145–151
and glutamate receptor genes have been
favoured by many investigators.
296,297
However, de-
spite several isolated weak associations, only a type II
metabotropic receptor, GRM3 (mGluR3), meets the
criterion
172
of association in three independent
studies. GRM3 maps to 7q21–22, not a locus high-
lighted in either meta-analysis.
164,165
The first, equi-
vocal, report of GRM3 association with schizophrenia
came in a German study. In 265 patients and 227
controls, an increased frequency of a SNP in exon 3
was found; however, the same paper also reported a
nonreplication in a second case–control population
(288 patients, 162 controls), and in 128 family trios.
298
Fujii et al,
299
in a case–control analysis of six SNPs in
100 Japanese patients and 100 controls, found
association to another SNP in intron 3, and to various
two and three marker haplotypes containing this SNP,
especially those spanning introns 3–5. Egan et al
300
genotyped seven common SNPs, including the posi-
tive ones from the earlier studies, in the Weinberger
lab dataset consisting then of 217 mostly Caucasian-
American families, and also the Caucasian (n ¼ 67)
and African-American (n ¼ 51) family subsets of the
NIMHGI. There was significant association to a SNP
in intron 2, and trends for association with the
positive SNPs from the earlier studies, together with
strong association (P
o0.0001) to common three and
five marker haplotypes that included them. Trends for
association (P ¼ 0.03–0.07) were also found for SNPs
in the NIMHGI samples. Egan et al
300
also searched for
evidence that the intron 2 variant associated with
schizophrenia either causes or monitors a change in
GRM3 function. They found that the allele was
associated, even in normal individuals, with impair-
ments commonly seen in schizophrenia, including
poorer episodic memory and attention, abnormal
prefrontal and hippocampal activation with fMRI,
and reduced prefrontal NAA signal measured with
MR spectroscopy. Also, in post-mortem human DPFC,
there was weak evidence for genotype effects on
GRM3 expression, and a strong inverse association
between the high-risk GRM3 allele and mRNA for the
glial glutamate transporter EAAT2. These findings
suggest direct and indirect influences of GRM3
variation upon the regulation of synaptic glutamate,
consistent with the known roles of GRM3 in such
processes.
301,302
Other aspects of GRM3 biology strengthen its
candidacy as a schizophrenia gene. It is a hetero-
ceptor modulating serotonin and dopamine transmis-
sion
and
associated
effects.
301,303,304
Type
II
metabotropic glutamate receptor agonists (GRM2
and 3) block the behavioural and cognitive effects of
NMDAR antagonism.
305
The peptide neurotransmitter
N-acetylaspartylglutamate (NAAG; which is hydro-
lysed to produce NAA and glutamate), is itself a
GRM3 agonist and has NMDAR activity.
306
These
findings link GRM3 with models of schizophrenia
centred
around
NMDAR
transmission
and
NAAG.
146,147,149,307,308
Consistent with these roles,
GRM3 is expressed in many neuron populations,
with a predominantly presynaptic localization, as
well as being expressed in astrocytes and oligoden-
drocytes.
309–315
Thus, convergent data implicate
GRM3 as a schizophrenia susceptibility gene and
suggest that the mechanism involves an alteration in
prefrontal and hippocampal glutamate neurotrans-
mission and the functioning of these regions. How-
ever, further positive associations and identification
of a functional variant that convincingly explains the
association are needed. Schizophrenia itself does not
affect GRM3 mRNA or protein levels in the
DPFC,
312,314
or GRM3 mRNA in thalamus
316
or
hippocampus (B Lipska, DR Weinberger and J Klein-
man, unpublished). However, these studies have
not yet considered the possibility of cell-specific
alterations or alternative splicing. Moreover, studies
of GRM3 protein are confounded by antibody
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
52
Molecular Psychiatry
crossreactivity with GRM2. It would thus be pre-
mature to conclude that GRM3 involvement in
schizophrenia is not reflected, at least partly, by
altered expression.
G72 (and DAAO)
The novel gene G72 was cloned from a 5 MB ‘gene
desert’ in the 13q linkage region after construction of
a dense LD map of SNPs across the region.
317
Following annotation and in vitro translation, the
gene was shown to encode a 150 þ amino-acid
protein with little evolutionary homology, and to be
part of a larger gene on the opposite DNA strand,
called G30. Several SNPs and haplotypes in this
region were found to be associated with schizophre-
nia in a French-Canadian case–control sample, and
one of these SNPs also showed association in a
Russian case–control sample.
317
Biochemical experi-
ments revealed that G72 protein activated a second
protein,
D
-amino acid oxidase (DAAO), which was
known to be involved in the metabolism of
D
-serine,
an agonist at the glycine modulatory site of the
NMDAR.
318
This made both genes attractive glutama-
tergic candidates for many of the same reasons
mentioned with regard to GRM3. Furthermore, the
authors reported that four SNPs in DAAO (located at
12q24) were themselves associated with schizophre-
nia in the French-Canadian sample, along with some
indication that SNPs in DAAO and G72 might act in
combination to influence schizophrenia risk.
317
Asso-
ciation of both genes to schizophrenia was confirmed,
in a study of seven G72 SNPs and three DAAO SNPs,
in a German case–control study of 299 patients and
300 controls.
319
However, the alleles were not the
same as those reported by Chumakov et al,
317
the
strongest association for G72 was with a different, and
under-represented, haplotype, and the DAAO asso-
ciations were with the opposite alleles. This mixture
of replication in a broad sense (ie to variation in the
gene) but nonreplication in detail (ie to a particular
allele or haplotype or to risk v. ‘protective’ haplo-
types) is perplexing and reminiscent of some of the
data with other genes. However, further evidence for
G72 as a risk factor for schizophrenia has emerged. A
Han Chinese study
320
of G72 in 233 trios found
significant overtransmission of two of the original
SNPs, and a haplotype including all three SNPs,
consistent with the original report.
317
Similarly, a
small study has reported association of several G72
SNPs and haplotypes, but not those in DAAO, with
childhood-onset schizophrenia.
321
Thus, in total, the
genetic data are suggestive for G72 (and it passes the
‘three replications’ threshold
172
), though much less so
for DAAO (which does not). In the Weinberger lab
schizophrenia datasets, Goldberg et al
322
found no
significant associations to 11 SNPs in G72 nor to five
in DAAO, but they did observe that the positive SNPs
in the study by Chumakov et al
317
are associated in
the predicted direction with cognitive and physiolo-
gical abnormalities related to prefrontal and hippo-
campal function in schizophrenia. This suggests that
G72 gene variation may show greater penetrance for,
or be more directly related to, such intermediate
phenotypes and that G72 may militate towards the
emergence of schizophrenia via disruption of func-
tion in these cortical systems (see below), akin to the
findings for GRM3, COMT, and DISC1.
DAAO is localized in peroxisomes in astrocytes and
some neurons in the rat brain,
323
but otherwise little is
known about G72 or DAAO expression. There is a
preliminary report of an equivocal increase of DAAO
mRNA in DPFC in schizophrenia.
324
Other genes
In this section, we briefly review some other genes
which do not yet meet the ‘three replication’ criterion,
but for which there is sufficient evidence to merit
mention, and which have neurobiological plausibility.
Calcineurin is a multifunctional calcium-depen-
dent serine/threonine phosphatase, known to be
centrally involved in many aspects of synaptic
plasticity, on both sides of the synapse.
325–327
It has
particular roles in glutamate and dopamine signalling
and
their
interactions,
including
regulation
of
DARPP32, a molecular node of convergence between
D1 and NMDAR signalling pathways.
328,329
Interest-
ingly, calcineurin appears to be absent from many
inhibitory neurons.
330
Based on evidence that calci-
neurin knockout mice exhibit deficits in behavioural
and pharmacological assays used as animal models of
aspects of schizophrenia (eg motor and social beha-
viour, PPI, responses to NMDAR antagonists),
331
Gerber et al
332
searched for associations between
schizophrenia and variations in four calcineurin
subunit genes in two family trio datasets. In an
American sample of 210 trios consisting in part of the
ethnically diverse NIMHGI dataset, weak evidence
was found for association to two of 16 SNPs in the
gamma catalytic subunit (PPP3CC), and to common
two and five marker haplotypes including these
SNPs. In a replication sample of 200 trios from South
Africa, described in minimal detail, there was a trend
for overtransmission of the same five marker haplo-
type, with a similar odds ratio (
B1.3). Calcineurin is
another attractive candidate gene because of its
functional roles,
325–327,331
and given the location of
the PPP3CC subunit gene close to NRG1, at 8p21, a
locus highlighted in the meta-analyses.
164,165
More-
over, calcineurin mRNA and protein expression is
decreased in schizophrenia in the hippocampus (SL
Eastwood and PJ Harrison, unpublished). However,
calcineurin expression is dynamic and altered in
many disease and experimental states, and so this
observation only incrementally adds to the candidacy
of the gene (c.f. RGS4), certainly until the association
with schizophrenia is replicated, and the functional
genetic variants identified.
The a7 nicotinic receptor gene (CHRNA7) is
implicated in schizophrenia by considerable, albeit
partially circumstantial, evidence. This includes the
modulation by nicotine of attentional and sensory
processing, such as those assayed by the P50
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
53
Molecular Psychiatry
response, and by the striking association between
smoking and schizophrenia.
333,334
Direct evidence for
involvement of CHRNA7 in schizophrenia comes from
the University of Colorado group, who first reported
that abnormalities of the P50 response were linked to a
region on 15q13–14 containing CHRNA7; this region
had also shown suggestive linkage to schizophrenia in
a few studies.
335
The same group later found that
combinations of SNPs in the CHRNA7 promoter
region were associated in a case–control analysis with
the abnormal P50 phenotype and possibly with
schizophrenia; several of these SNPs appeared func-
tional in an in vitro gene expression assay.
336
CHRNA7
is involved both pre- and postsynaptically in mod-
ulating dopamine and glutamate signalling,
337–340
and
is recruited to the synapse by NRG1.
341
It is expressed
widely,
342
and prominently in inhibitory interneur-
ons.
333,339,343
CHRNA7 expression, measured as im-
munoreactivity or binding site densities, is reduced in
schizophrenia in several areas, including hippocam-
pus,
344
thalamus,
345
frontal cortex,
346
and cingulate
cortex.
347
The biological candidacy of CHRNA7 is
therefore impressive, but its impact on genetic risk
remains uncertain prior to independent replication.
Genetic analyses of CHRNA7 are complicated by
partial duplication of the gene.
348
Proline dehydrogenase (PRODH2) was identified as
a possible susceptibility gene after extensive associa-
tion analysis of SNPs in genes within a 1.5 Mb block
of the VCFS deletion region on 22q11. This revealed
several missense SNPs within a locus containing
PRODH2, which were associated with schizophrenia
in an American sample of 107 trios, part of the
population from the study of calcineurin (above) and
consisting primarily of the NIMHGI datasets.
349
A
three marker haplotype spanning three 3
0
exons, but
seemingly independent of the missense SNPs, was
also positive in an ethnically diverse childhood-onset
schizophrenia sample (29 trios) and in a small adult
case–control dataset from South Africa. In the two
adult samples, the power of the association was
enhanced by restricting the analysis to cases with
earlier ages of onset, and the odds ratio for over-
transmission of the high-risk haplotype in these cases
was unusually high (44). Liu et al
350
then demon-
strated that PRODH2 has a duplicated pseudogene
about 1.5 Mb downstream which contains a few of the
missense SNPs they had associated with schizophre-
nia, raising the interesting question of whether the
variation in PRODH2 was the result of conversion
between the real and pseudogene sequences. Also, the
congenital syndrome of hyperprolinemia, caused by
PRODH2 deficiency, may be weakly associated with
schizophrenia.
351
Some functional data support
PRODH2 as a candidate gene, notably from the
PRODH knockout mouse,
352
which has PPI deficits
and decreased levels of glutamate and GABA in some
brain regions, consistent with the role of the enzyme
in regulating proline levels, which in turn influence
glutamate metabolism and release.
353,354
However, the
status of PRODH2 as a schizophrenia susceptibility
gene remains equivocal, as association has not been
replicated, either in a Chinese population (albeit only
one of the positive SNPs
349
was studied),
355
or in a
Japanese sample,
356
or in a large UK/Irish case–
control group, which included early onset cases and
several cases of VCFS with psychosis, along with 55
Bulgarian trios.
357
These authors subsequently se-
quenced the entire gene in 14 patients and failed to
reveal any additional associated SNPs.
358
PRODH2
mRNA is unaltered in the DPFC in schizophrenia.
222
Emamian et al
359
used a combination of experi-
ments to implicate Akt1 (protein kinase B) as a
susceptibility gene. Starting with the broad concept
that kinases and phosphatases are candidate genes,
they measured the abundance of several such proteins
in lymphocytes from patients and controls. After
finding Akt1 to be consistently altered (reduced) in
schizophrenia, they showed that this also occurred in
the hippocampus and frontal cortex of two case–
control series, and was accompanied by decreased
phosphorylation of glycogen synthase kinase 3b
(GSK-3b), a target of Akt1 and a molecule of prior
interest in schizophrenia.
360
Genetic association was
then found between an Akt1 haplotype and schizo-
phrenia in 268 affected families, with the risk
haplotype being associated with lower Akt1 expres-
sion in lymphocytes. Finally, Akt1 knockout mice
were shown to be more sensitive to amphetamine-
induced PPI disruption. The Akt1 study
359
serves as
another good illustration of how putative suscept-
ibility genes for schizophrenia may be identified
using an hypothesis-driven strategy combined with
convergent,
multifaceted
experimental
evidence.
However, the Akt1 association with schizophrenia
remains to be confirmed, and caution must be exerted
when postulating the biological mechanism explain-
ing the association, as Akt1 has multiple and diverse
functions.
361
How does genetic variation confer susceptibility to
schizophrenia?
Simplistically, genetic variation affects disease sus-
ceptibility in one of two ways. Either it changes the
structure of the encoded protein (eg by an amino-acid
substitution or frame-shift mutation) or it alters the
expression of the gene (eg by altering some parameter
of transcription or translation) and thereby the
amount or distribution of the protein. Both processes,
which in reality are not mutually exclusive, ulti-
mately exert their effects by affecting the function of
the protein. The COMT val158met polymorphism is a
prime example of the former type. Variation in the
other susceptibility genes may also come into this
category, but this would require that the SNPs
currently associated with the disease, virtually all of
which are noncoding, are acting as markers for coding
variants; this will become increasingly unlikely as the
genes are resequenced more extensively in affected
individuals and as no unique transcripts or protein
isoforms are found. Instead, it seems likely that many
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
54
Molecular Psychiatry
of the associations, if genuine, come into the category
of altering expression of the gene. This is a more
complex and subtle manifestation of genetic predis-
position, and may be exerted in many ways. Promoter
variants can markedly impact on transcriptional
activity of the gene.
362–365
Intronic SNPs can also
affect transcription, or alter splicing or mRNA
stability and thus the relative abundance and propor-
tions of isoforms;
363,366
the differing functions as-
cribed to NRG1 isoforms mentioned above illustrates
the potential pathogenic as well as physiological
consequences of this.
367
SNPs in the 3
0
UTR may alter
mRNA stability and thence translation.
368,369
Even
conservative exonic SNPs, usually considered func-
tionless, can alter mRNA structure and transla-
tion.
370,371
Finally, the effects of individual SNPs
cannot be studied alone, since they are influenced
by haplotype background.
372
As if these molecular
complexities were not enough, studies cannot rely
solely on in vitro or animal models, because some
aspects of gene regulation may be unique to the
human brain in vivo, and so must include post-
mortem research with all the practical problems that
entails. It must also be borne in mind that altered
expression of susceptibility genes need not occur only
because of genetic variants that are associated with
the disease. The susceptibility genes may encode
molecules that represent convergent nodes in signal-
ling pathways that can be affected via numerous other
entry points, including variations in other genes that
feed into these pathways, and lead to compensatory
or secondary changes. Finally, it is worth reiterating
that the relationship between genotype and pheno-
type may also be complicated by epigenetic factors
(heritable factors without sequence variation, eg,
changes in DNA methylation and chromatin struc-
ture), that regulate gene activity and which have been
advocated to be important in schizophrenia.
373–375
Overall, therefore, understanding in molecular
terms how genetic variation confers susceptibility to
schizophrenia may prove a deceptively difficult task:
first the ‘true’ risk variant(s) in each gene must be
identified, and then the way in which a variant alters
the function of the encoded protein must be estab-
lished. Even when this has been achieved, the picture
will still be incomplete, since there will likely be
Cellular neuropathology
Cognitive and other trait features
Dysregulated dopaminergic
transmission
Psychotic symptoms
GRM3
COMT
G72
PPP3CC
NRG1
Dysbindin
RGS4 PRODH
DAAO CHRNA7
DISC1
Akt1
Neurotransmission
Plasticity
Synaptogenesis
Figure 1
Schizophrenia as a genetic disorder of the synapse. Schematic representation of the putative common effect of
schizophrenia susceptibility genes on the plasticity and functioning of synapses. The proximate explanation for this effect
likely varies for each gene in several dimensions, such as temporal order and molecular target. Roughly reflecting the timing
factor, the genes are shown arranged from left (acute effects on neurotransmission) to right (primary effects upon
synaptogenesis or longer-term synaptic plasticity). Those genes thought to have a major or preferential effect on NMDAR-
mediated glutamate transmission are shown in italics. The evidence implicating each gene in synaptic pathology is
summarized and referenced in the text. To keep the schematic simple, many complexities have been omitted: (1) The various
epigenetic and environmental factors which may act upon and interact with the genes, either directly (eg by affecting their
expression) or indirectly (eg by affecting the processes which the genes regulate). We have also omitted interactions between
genes, such as that already shown for G72 and DAAO. (2) The effect of susceptibility genes on synaptic pathology may not be
direct or exclusive, but occur in tandem with, or be mediated by, other genes, such as those independently implicated in
neurodevelopment and plasticity, for example, reelin, BDNF, Wnts. (3) The susceptibility genes may each be associated with
a different anatomical or molecular profile of neuropathology (c.f. the in vivo data suggesting that DISC1 and GRM3 variants
are associated with hippocampal function, and COMT with the prefrontal cortex), and may help explain the heterogeneity of
post-mortem findings. There may also be clinical heterogeneity. (4) A distinction is made between ‘structural’ and
‘functional’ consequences of the genes, in part to emphasize that conventional neuropathological findings are likely to be
correlates of the former, whereas neurochemical fluctuations, for example, the striatal hyperdopaminergia associated with
acute psychosis, need not be. However, the causal relationship between these two facets of pathophysiology is unknown, and
it could be that one leads to the other, or that the two are independently linked to the inferred primary synaptic dysfunction;
in any event, as discussed in the text, the dichotomy is ultimately a false one and is really a matter of degree.
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
55
Molecular Psychiatry
important gene–gene, gene–environment and pro-
tein–protein interactions to be studied, not to men-
tion the protean effects on downstream molecular and
neural system processes. The discovery of schizo-
phrenia susceptibility genes may well be looked back
upon as a relatively trivial task compared to the
subsequent elucidation of how they operate.
Schizophrenia as a complex genetic disorder of
cortical microcircuits
Undaunted by the preceding paragraph, we turn
finally to perhaps the most interesting question of
all: what does the identity of the genes tell us about
the nature of schizophrenia? While any answer is in
the realm of speculation, we would opine, parsimo-
niously, that the susceptibility genes influence brain
function directly, in a way which is consistent with
existing neurobiological understanding of schizo-
phrenia and with the neuropathological clues men-
tioned above, and, furthermore, that the genes may
confer susceptibility by converging on a shared
pathophysiological process. Specifically, it has been
noted
376
that most if not all the susceptibility genes
impact upon the molecular biology of the synapse, in
keeping with the view of schizophrenia as a disorder
of synaptic signalling. The additional genes reported
since this proposal was made (calcineurin, Akt1,
GRM3) are consistent with it. The genetic influences
on the synapse include effects on receptors (eg GRM3,
CHRNA7, G72), signal transduction (RGS4), and
regulation of plasticity and synaptogenesis (NRG1,
dysbindin, DISC1, calcineurin). Figure 1 is a highly
simplified schematic of these relationships. Glutama-
tergic synapses and processes appear to be particu-
larly affected,
376,377
notably NMDAR signalling, which
is influenced in one way or another by most if not all
of the current catalogue of putative susceptibility
genes (Figure 2). However, there are also direct links
for several of the genes with dopaminergic (viz.
COMT) and GABAergic systems,
333,378,379
and the
latter may itself harbour susceptibility genes. Thus,
when considered along with the manifold functional
and anatomical connections between these transmit-
ter systems, it is already clear that there is no one
single target upon which the genes act, nor any one
cell type or compartment wherein they are expressed.
In turn, therefore, although the genes currently appear
to disproportionately impact glutamate and NMDAR,
the genetic basis of schizophrenia is most unlikely to
reside in any one transmitter or receptor, and the
disease will not prove reducible to, or be genetically
explained by, a single molecular processs or neuro-
transmitter signalling system.
The evidence that schizophrenia susceptibility
genes affect diverse synaptic processes suggests that
it will not be synapses per se but the neural circuits in
which they participate which will prove to be the
appropriate explanatory level to understand how the
genetic influences operate. This is consistent with the
view that the disorder is fundamentally one of
abnormal information processing at the highest level,
and such abnormalities are probably best understood
in terms of malfunction of cortical microcircuits.
218
In
other words, the real locus of genetic convergence, if
there is one, is downstream of any specific molecule
or synaptic event per se, and resides in some
integrative activity or emergent property of the
circuits subserving the core cognitive elements
affected in schizophrenia, for example, by impairing
the signal-to-noise ratio and decreasing the efficiency
of information processing.
218,380
This makes it con-
ceivable that various combinations of susceptibility
genes can converge on synaptic processing in these
microcircuits to effect a common pattern of dysfunction
and emergent symptoms, though the specific combi-
Figure 2
Schizophrenia genes within cortical neural circuits. Part of a canonical cortical circuit is shown in the bottom left
panel. The main panels (A and B) shows the primary cellular and subcellular location(s) of the proteins encoded by
schizophrenia susceptibility genes (purple on yellow) within the circuit. (A) An excitatory synaptic terminal (eg of a
corticocortical pyramidal neuron, Schaffer collateral, or thalamic afferent), shown to the left in grey, contacts a dendritic
spine of an intrinsic pyramidal neuron (grey, to its right). A dopaminergic afferent (blue-green) is shown terminating on the
neck of the spine. A generic glial cell (green) is also shown apposed to the synapse. (B) An inhibitory interneuron (brown) is
shown terminating on the dendritic shaft (or soma) of the pyramidal neuron. Note that not all genes may be expressed at the
same time in the same cells. Minor locations for each protein have been omitted. The question mark denotes that the
distribution of DISC1 is particularly unclear. In the case of NRG1 (blue), its main signalling pathways are included (solid
arrows: direct actions; dashed arrows: downstream effects of ErbB activation), to illustrate the complexity of the interplay
between the various cellular elements and the different susceptibility genes which likely exists in vivo. Although this
diagram emphasizes location, the essential point is that the genes converge not upon any specific molecule or site but do so
at the level of the plasticity and functioning of the microcircuitry. Variations in the genes affect schizophrenia risk by
producing bottlenecks, that is, biasing the flux through specific molecular pathways, ultimately impairing optimal
functioning of the circuits and the behaviours they subserve. So, for example: (1) COMT modulates cortical dopamine
signalling via D1 receptors, which amplify NMDAR currents and are themselves recruited to the cell membrane by NMDAR
signals; (2) NRG1 modulates NMDAR and GABA
A
receptor expression and recruits CHRNA7 receptors to synapses; (3)
Dysbindin and PRODH regulate glutamate release; dysbindin is also involved in tethering GABA
A
and other receptors to the
PSD and may be important in vesicular trafficking of presynaptic glutamate; (4) Calcineurin and Akt1 shape intracellular
molecular pathways that are activated by excitatory inputs; (5) GRM3 interacts with NMDAR via modulation of glutamate
release and glial reuptake, and so on. For references see text. Additional abbreviations not defined in text: AMPAR, AMPA
subtype of ionotropic glutamate receptor; DA, dopamine;
D
-Ser,
D
-serine; GAD, glutamic acid decarboxylase; Glu, glutamate;
PSD, postsynaptic density.
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
56
Molecular Psychiatry
nation of genes and possibly alleles can vary across ill
individuals.
Returning to the other main theme of this review,
viz. the neuropathology of schizophrenia, the sus-
ceptibility genes have implications for how the data
should be interpreted. If the genes are, in one way or
another, influencing the properties of certain neural
circuits, then the morphological alterations are likely
a secondary manifestation (both in terms of causal
sequence and importance) of this developmental and
dynamic shift in the normal regulation of synaptic
connectivity and activity. There are already many
examples of an overlap between the susceptibility
genes and reported pathological features. For exam-
ple, the alterations in dendritic spines in schizophre-
nia may reflect the effects of mutiple genes on diverse
aspects of NMDA signalling, or perhaps, the close
relationship between calcineurin and spinophilin,
329
or that between Akt1 and reelin.
381,382
Similarly, the
influences of NRG1 signalling on oligodendrocyte
differentiation
383
and interneuron development
384
might contribute to the morphometric alterations seen
in these cell populations in schizophrenia. The same
principle would be predicted to govern the relation-
ship with pathology for subsequent susceptibility
genes which are discovered (eg under the 2p locus
Neuropathology and genetics of schizophrenia
PJ Harrison and DR Weinberger
57
Molecular Psychiatry
peak),
165
and also to apply in other disorders sharing
susceptibility genes and/or neuropathological fea-
tures with schizophrenia, for example, bipolar dis-
order,
100,385,386
autism,
387
and mental retardation
syndromes.
388,389
By the same token, the clinical
correlates of the genetic neuropathology of schizo-
phrenia seem more likely to be features which are
observed across broad diagnostic categories and
which are stable across time (eg neurocognitive
impairments) rather than the specific and fluctuating
psychotic symptoms of the syndrome.
Having indulged in this speculation upon how the
genes might drive the pathogenesis of schizophrenia,
we finish with some due caveats. First, the ideas are
vague, lacking the molecular elegance of disease
models built around a specific gene or biochemical
mechanism. Second, it is hard to envisage that any
brain disease, or any gene expressed in the brain,
could entirely lack effects on one or other aspect of
neural plasticity and functioning, and so the propo-
sals are inherently superficial. Third, the fact that no
abnormal proteins have been identified, and the
genetic variants are common (and vary between
studies), suggests that the disease process will prove,
in molecular terms, to be subtle, complex, and
fundamentally a quantitative trait rather than a
qualitative abnormality—just as is the case for the
genetics and the neuropathology. These issues mean
that though a web can be woven which ties all the
putative schizophrenia genes to synaptic plasticity,
NMDAR signalling, etc, it is not clear whether this is
what makes these genes relevant to schizophrenia. It
also means that much more evidence will be needed,
from genetic, neuropathological, and experimental
approaches, before this or any other incisive mole-
cular pathophysiological model can be established.
On the other hand, at this stage of research, the notion
that the neurobiology of schizophrenia might be
reducible to one or a few common pathways may be
a useful starting point, to be refined or refuted as
research progresses. A heuristic value has certainly
been apparent for the aforementioned b-amyloid
hypothesis
of
Alzheimer’s
disease,
which
has
been central in focusing pathophysiological and
pharmacotherapeutic strategies, even while debate
continues regarding its detailed specification
2
and
even its validity.
390
Finally, we note that despite its
unequivocal genes and overt neuropathology, even
Alzheimer’s disease research is not immune from the
genetic uncertainties being faced in schizophrenia.
391
Summary
Schizophrenia continues to lack a diagnostic neuro-
pathology, convincing causative genetic mutations,
and even unequivocally replicated associations with
the same alleles or haplotype within each gene.
Nevertheless, the weight and convergence of evidence
of susceptibility genes for schizophrenia cannot be
dismissed. Even if some genes prove to be false
positives, others will remain and provide important
insights into the pathogenesis and pathophysiology of
psychosis. Genes represent mechanisms of disease,
and in a field previously based on phenomenology,
this is a sea change in the science of schizophrenia.
Future neuropathological investigations can now take
genetic background into account, while studies
relating genetic variation to schizophrenia and its
intermediate phenotypes will be complemented by
investigations characterizing the distribution, abun-
dance, and potential modifications of the gene
products. Together these approaches should allow
identification of the molecular and cellular mechan-
isms that link the susceptibility genes to the neuro-
biology, both structural and neurochemical, although
the scale of this task should not be underestimated. In
the process, the research will determine the extent to
which the genes operate in a convergent way, whether
they do in fact impact primarily on synaptic plasticity
in the service of microcircuit information processing,
and it will allow this suggestion to be mechanistically
specified. Both the genes themselves and the bio-
chemical pathways in which they participate will be
attractive, though not necessarily tractable, therapeu-
tic targets. What cannot be disputed is that the
discovery of susceptibility genes for schizophrenia
changes the research landscape and its horizons
profoundly and permanently.
Acknowledgements
We thank the many people who have contributed to
the ideas and data presented here, especially Jingshan
Chen, Sharon Eastwood, Michael Egan, Joel Klein-
man, Amanda Law, Barbara Lipska, Leah Sartorius,
Cindy Shannon-Weickert, Richard Straub, and Liz
Tunbridge. We are grateful to Leah Sartorius for
creating Figure 2. We apologize to all the researchers
whose work is not cited for lack of space. The
Harrison lab is supported by the Stanley Medical
Research Institute and the Wellcome Trust.
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