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Genetic Risk for Schizophrenia: Convergence


on Synaptic Pathways Involved in Plasticity
Article in Biological Psychiatry December 2014
DOI: 10.1016/j.biopsych.2014.07.011

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Review

Biological
Psychiatry

Genetic Risk for Schizophrenia: Convergence


on Synaptic Pathways Involved in Plasticity
Jeremy Hall, Simon Trent, Kerrie L. Thomas, Michael C. ODonovan, and Michael J. Owen
ABSTRACT
Recent large-scale genomic studies have revealed two broad classes of risk alleles for schizophrenia: a polygenic
component of risk mediated through multiple common risk variants and rarer more highly penetrant submicroscopic
chromosomal deletions and duplications, known as copy number variants. The focus of this review is on the
emerging ndings from the latter and subsequent exome sequencing data of smaller, deleterious single nucleotide
variants and indels. In these studies, schizophrenia patients were found to have enriched de novo mutations in genes
belonging to the postsynaptic density at glutamatergic synapses, particularly components of the N-methyl-Daspartate receptor signaling complex, including the PSD-95 complex, activity-regulated cytoskeleton-associated
protein interactors, the fragile X mental retardation protein complex, voltage-gated calcium channels, and genes
implicated in actin cytoskeletal dynamics. The convergence of these implicated genes onto a coherent biological
pathway at the synapse, with a specic role in plasticity, provides a signicant advance in understanding
pathogenesis and points to new targets for biological investigation. We consider the implications of these studies
in the context of existing genetic data and the potential need to reassess diagnostic boundaries of neuropsychiatric
disorders before discussing ways forward for more directed mechanistic studies to develop stratied, novel
therapeutic approaches in the future.
Keywords: Actin, ARC, Genetics, NMDA, Schizophrenia, Synapse.
http://dx.doi.org/10.1016/j.biopsych.2014.07.011
The primary motivation for studying the genetics of schizophrenia has been to illuminate the biological and pathological
processes underlying this debilitating condition (1). Schizophrenia is a highly heritable disorder (2), leading to the
hypothesis that genomic studies provide the best route to
uncovering etiology and advancing treatment (3). However, the
complex genetics of schizophrenia have proved remarkably
difcult to unravel, requiring major technical advances and the
collaborative efforts of many investigators to yield progress (4).
As a result of these efforts, recent years have seen substantial
progress in understanding the genetic architecture of schizophrenia, primarily through large-scale genomic approaches
(5,6). While many aspects of genetic risk for the disorder
remain to be fully interpreted, it has become increasingly clear
that genes expressing proteins involved in the regulation of
synaptic plasticity are particularly affected in schizophrenia (7)
and also in related disorders such as autism spectrum
disorder (ASD) (8,9). Here, we briey review our current
understanding of the genetic architecture of schizophrenia,
before concentrating on recent studies of de novo and rare
mutations in schizophrenia that have begun to implicate
specic biological pathways at the synapse in pathogenesis.

THE EMERGING GENETIC ARCHITECTURE OF


SCHIZOPHRENIA
Major progress in understanding the genetic architecture of
schizophrenia has been leveraged through the application of

whole-genome array-based association methods in largescale collaborative studies. One of the early major insights
into the genetics of schizophrenia was the signicant polygenic component of risk for the disorder mediated through
multiple risk variants, each individually contributing a very
small component of risk but collectively accounting for a
signicant proportion of overall burden for the disorder
(1015). Moreover, an appreciable fraction of that risk was
shared with other psychiatric disorders, in particular bipolar
disorder (10). The second is that individually rare submicroscopic chromosomal deletions and duplications, known as
copy number variants (CNVs), can also increase risk for the
disorder in affected individuals with odds ratios that are much
higher than those seen for common risk variants (1619). While
these array-based approaches fundamentally advanced our
understanding of the genetic architecture of the disorder, the
current robustly implicated loci collectively account for only a
small proportion of overall risk (20,21). Notably, array-based
methods are not well powered to detect the effect of rare, but
potentially impactful, deleterious single nucleotide variants
(SNVs) and other small variants such as indels (22). This issue
has recently begun to be addressed by large-scale sequencing approaches, currently restricted to exome sequencing,
which have the resolution to detect rare SNVs and indels
contributing to risk (6,23). One particularly illuminating method
to study rare variants (including both CNVs and SNVs) has
been the use of case-parent trio designs to identify rare de
novo variants that occur in patients but not in either of their

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& 2015 Society of Biological Psychiatry
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Genetic Risk for Schizophrenia

biological parents, potentially enhancing the likelihood that


they are of pathogenic importance. This approach has been
successful at implicating a role for loss-of-function de novo
mutations in ASD and intellectual disability (ID) (2427). The
conclusions that can be derived from similar studies in
schizophrenia populations have previously been less clear,
possibly due to limited sample sizes and/or differences in
analysis methods (28,29). However, very recently, the study of
de novo variants in schizophrenia using trios and exome
sequencing in case-control samples, combined with
pathway-based analysis, has begun to produce some strikingly convergent ndings regarding genetic pathways implicated in schizophrenia and these studies will be the focus of
this review (30,31).

GENETIC FINDINGS FROM STUDIES OF DE NOVO


AND RARE MUTATIONS IN SCHIZOPHRENIA
To investigate de novo CNV mutations in schizophrenia, Kirov
et al. (7), building on previous evidence of elevated rates of
CNVs (16,17,32), investigated de novo CNV mutations in over
600 schizophrenia parent-proband trios using array-based
methods (7). The study identied de novo copy number
variants in approximately 5% of cases, a rate 2 to 3 times
higher than in control subjects depending on the size of the
CNV. Mutations occurring de novo included previously identied risk CNVs at 3q29, 15q11.2, 15q13.3, and 16p11.2, as
well as recurrent likely pathogenic CNVs affecting discs large 2
(DLG2) and Eu-HMTase1 (EHMT1). However, the majority of
the identied CNVs affect more than one gene, and along with
the rarity of most individual CNVs, this makes it difcult to
determine the biological processes implicated by these mutations. To overcome this problem, Kirov et al. (7) used a
systems-based statistical approach to identify biological pathways enriched for genes within the de novo CNV loci. Using
gene sets constructed from experimental proteomics, they
identied signicant enrichment at the CNV loci for genes
involved in the postsynaptic density (PSD) proteome at
synapses. This enrichment was largely explained by genes
encoding components of the N-methyl-D-aspartate (NMDA)
receptor signaling complex, including members of the disks
large family of membrane associated guanylate kinases, and
synaptic protein interactors of the activity-regulated cytoskeleton-associated protein (ARC) (also known as Arg3.1)
(7,33,34). Other genes within schizophrenia-implicated CNVs
included CYFIP1, a recently characterized protein binding
partner of the fragile X mental retardation protein (FMRP),
which together target and regulate the protein translation of a
number of identied messenger RNAs (mRNAs) including ARC
itself (35,36). Enrichment for genes encoding NMDA receptor
complex proteins was further substantiated in analysis of
CNVs from a large case-control dataset, although association
with ARC was not seen in that analysis (7).
More recently, the same trio sample analysis has been
coupled with exome sequencing to identify smaller rare de
novo mutations associated with schizophrenia (30). Notably,
this approach also revealed an excess of smaller deleterious
de novo mutations in schizophrenia affecting the components
of the NMDA receptor signaling complex and synaptic
protein interactors of ARC, as well as an enrichment of

mutations in the targets of the FMRP complex. A genomewide, hypothesis-free analysis of this dataset based on gene
ontology annotations additionally revealed a signicant enrichment in schizophrenia for mutations in genes involved in actin
lament bundle assembly (F-actin polymerization), a highly
dynamic process implicated in the regulation of dendritic spine
morphology and synaptic plasticity (37), which interacts with,
and is regulated by, NMDA receptor-associated signaling and
ARC. The nding of an enrichment of rare variants in PSD
complex genes in schizophrenia was further supported in an
independent large case-control exome sequencing study
in which rare disruptive mutations were enriched in the
NMDA receptor-associated PSD-95 protein complexes,
ARC-interacting proteins, and targets of the FMRP (31). The
latter study by Purcell et al. (31) also identied a signicant
enrichment of rare mutations in voltage-gated calcium ion
channels (VGCCs), a class of genes known to also be central
to the regulation of plasticity and previously strongly implicated in the pathogenesis of schizophrenia and related disorders through genome-wide association studies of common
variants (3841).

TOWARD MECHANISMS OF DISEASE


While the currently identied rare variants in schizophrenia still
only account for a small proportion of overall risk, the
convergent ndings in these studies point strongly to the
involvement of a related group of genes and proteins in the
pathogenesis of schizophrenia. It is unlikely that these represent the only route to increased risk for this highly complex
disorder, as the identied pathways were largely identied on
the basis of empirical testing of prior hypotheses regarding the
importance of synaptic processes in disease. However, the
emergence of one clear pathway of risk would be a signicant
advance in understanding pathogenesis and point to new
targets for biological investigation.
A notable feature of these ndings is not only their
consistency across different studies but also their convergence into a coherent set of biological processes involved in
the regulation of plasticity, particularly at glutamatergic synapses (Figure 1). It is worth, therefore, considering briey some
ways in which the implicated genes and proteins are functionally interconnected. The NMDA receptor complex at the
PSD, as well as VGCCs, play a central role in the control of
associative plasticity at the synapse through the regulation of
calcium entry (4244). The entry of calcium ions into the
postsynaptic dendrites through NMDA receptors and VGCCs
leads to the activation of a series of second messenger
systems, one consequence of which is altered regulation
of gene expression through the activation of transcription
factors including cyclic adenosine monophosphate response
element-binding protein (45,46). Through this mechanism, the
activation of NMDA receptor and VGCC signaling results in the
onset of gene expression at activated synapses, including
rapid transcription of the Arc gene, as well as other regulated
genes, including BDNF (47,48). In rodents, Arc mRNA is one of
a relatively small number of dendritically targeted mRNAs that
accumulate in the region of activated synapses (47,4951).
Translation of Arc can thus occur in response to local
demands by a process that is regulated by translational

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53

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Genetic Risk for Schizophrenia

Figure 1. Converging synaptic pathways implicated in schizophrenia risk.


Genes enriched for de novo mutations
VGCC
in schizophrenia or enriched for rare
disruptive mutations in cases relative to
control subjects were found to conPresynaptic
neuron
Glutamate
verge on common biological pathways:
the N-methyl-D-aspartate receptor
VGCC
NMDAR
mGluR
AMPAR
(NMDAR) signaling complex including
the PSD-95 complex, activity-regulated cytoskeleton-associated protein
Postsynaptic neuron
(ARC) interactors, the fragile X mental
retardation protein (FMRP) complex,
NMDAR
voltage-gated calcium channels (VGCCs),
signalling
and F-actin polymerization (7,30,31).
complex
These ndings implicate interconnected biological mechanisms predoSynaptic receptor trafficking
minantly at the postsynaptic density
of glutamatergic synapses and their
ARC
Translation
role in regulating plasticity. Synaptic
ARC
protein
G-actin
mRNA
activity triggers the entry of calcium
into the postsynaptic dendritic spines
ARC
interactors
directly through VGCCs and via glutamate-activated NMDA receptors,
FMRP-CYFIP1
resulting in the subsequent activation
F-actin
Dendritic
of second messenger systems and an
Dendrite
transport
increase in ARC messenger RNA
(mRNA) transcription (45,47). GlutaNucleus
matergic activation of metabotropic
ARC mRNA
ARC
glutamate receptor (mGluR)1/5 is
Translation
Soma
protein
similarly able to initiate ARC mRNA
transcription (84). ARC mRNA is transported to activated synapses via the
FMRP-containing messenger ribonuAMPAR mRNA
cleoprotein complex, which is dependent upon the stabilization of F-actin
(53). Meanwhile, the translation of ARC
is both positively regulated by glutamate-activated mGluR5 (63,84) and under the negative control of the FMRP-CYFIP1 complex (35). ARC protein is able to affect
plasticity through the regulation of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) synaptic trafcking through 1) its effects on F-actin
polymerization and interaction with dynamin, endophilin2/3, and colin (57,6063); and/or 2) the ability of local ARC protein in the soma to be imported back into the
nucleus and block AMPA receptor mRNA transcription (64). In this way, the local, activity-dependent control of ARC mRNA and protein levels in the postsynaptic
region provides an elegant focal point for moderating both the molecular and structural events at glutamatergic synapses that are central to plasticity (85). Ca21,
calcium ions.

inhibition by the FMRP-CYFIP1 protein complex (35), with


resultant localization of Arc protein to spines and the PSD (52).
Arc has multiple roles in controlling plasticity (53), and blocking Arc activity using antisense oligodeoxynucleotides (ODNs)
or transgenic approaches impairs major forms of plasticity,
including long-term potentiation (LTP) and long-term depression, and associative memory processes (54,55).
Synaptic Arc has a major inuence on F-actin polymerization and spine dynamics. For example, decreasing Arc
levels by infusion of Arc antisense ODNs into the hippocampus inhibits brain-derived neurotrophic factor induced LTP
and results in a decrease of the formation of F-actin at
activated synapses (56). Furthermore, this effect of Arc antisense ODN infusion on LTP was inhibited by the infusion of
the F-actin stabilizing drug jasplakinolide (56), conrming a
close link between Arc expression and the regulation of
F-actin dynamics associated with plasticity. The effects of
Arc on F-actin polymerization are likely to impact not only
on spine morphology but also on the maintenance of the
molecular organization of the PSD mediated through F-actin
dynamics (53). Arc also regulates -amino-3-hydroxy-5-

54

methyl-4-isoxazole propionic acid receptor trafcking in the


synapse (57), a process that is central to the long-term
stabilization of plastic changes (58,59). While the exact mechanism by which Arc mediates its effects on F-actin polymerization and surface -amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid receptor levels, and the relationship between
these functions, remains to be claried, the interaction of Arc
with proteins, including dynamin, endophilin2/3, and potentially
colin, may play a role (57,6064). Nevertheless, the local
activity-dependent control of Arc levels in the postsynaptic
region provides an elegant mechanism for modulating and
stabilizing the molecular and structural events at glutamatergic
synapses that are central to plasticity to the sparse spatial and
temporal coding of information storage critical for associative
memory (65). The Arc pathway therefore emerges as a key
regulator of structural and molecular plasticity, as well as a
central player in genetic risk for schizophrenia.
The pathways implicated in genetic studies of de novo
mutations and rare variants in schizophrenia thus converge on
related postsynaptic molecular processes intimately involved
in the regulation of synaptic plasticity. However, some

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implicated genes, including those encoding VGCCs and


Neurexin-1 (an associated CNV locus), also exert effects on
plasticity presynaptically, pointing to a broader association of
risk with synaptic regulation (66,67). The identication of
convergent biological pathways involved in synaptic plasticity
as one route to pathogenesis in schizophrenia provides a
framework for future functional studies of the disease and
eventually potentially to new routes to therapy.

FROM GENETICS TO BIOLOGY


The emergence of a convergent pathway involved in risk for
schizophrenia is an important precursor to meaningful functional studies. However, a number of key issues need to be
addressed to advance our understanding of the generalizability of these ndings and to determine how genetic lesions in
these pathways enhance risk for schizophrenia and related
disorders. Some of these are considered in turn here.
First, the relationship of the ndings from studies of rare de
novo mutations to other forms of genetic risk for schizophrenia
needs to be claried. While many associated CNVs involve
genes clearly involved in the regulation of plasticity, the link is
less clear for other variants (7,30,31). In particular, large
genome-wide association studies have demonstrated the
involvement of a large number of common variants of small
effect in risk for schizophrenia and conrm a substantial
polygenic component of risk for the disorder (6,12,39,41).
While some of the multiple genome-wide signicant loci have
roles in plasticity and synaptic function, this link is not so clear
for many of the other associated loci. Perhaps most crucial will
be to ascertain the net effect of overall polygenic risk of
common variants, although this will require new approaches
including the assessment of the effects of polygenic burden in
stratied populations (41,68). An issue of interest will be to
determine whether polygenic burden impacts on similar
molecular, cellular, and functional processes to those implicated by rare/de novo variants or implicate separate pathways
involved in risk.
Second, the degree to which the associated pathways
cross current diagnostic boundaries remains to be fully
established. Synaptic genes have been implicated in a range
of neuropsychiatric conditions including ASD (8,9) and ID
(26,69). In line with these ndings and those from studies of
CNVs (70), Fromer et al. (30) found evidence for an overlap of
de novo risk variants in schizophrenia with those seen in ASD
and ID and reported evidence for a gradation of mutational
severity with ID . ASD . schizophrenia as predicted by a
recent model of the relationship between these disorders (71).
However, Purcell et al. (31) reported no evidence for overlap
between these disorders at the individual gene level, though all
disorders showed enrichment for FMRP targets. Further
studies will be required to fully elucidate the genetic relationship between these conditions. However, it is already clear
that there is much greater overlap in terms of etiological
factors than is accounted for in current classication systems
(72).
Third, we must accept that synaptic plasticity is far too
general a construct to signicantly advance mechanistic
understanding or treatment (73,74). However, the identication
of specic genetic lesions likely affecting plasticity in the

disorder opens up the possibility of examining in a more


precise fashion how plasticity is disturbed in patients. Is there
a convergent synaptic signature associated with molecular
risk for schizophrenia and related disorders? If so, what is its
nature and what are the best models in which to delineate
such changes? Alternatively, is there a range of alterations of
synaptic function in different individuals? Clearly, the degree of
generalizability of the ndings in terms of functional effects at
the synapse will have a major impact on the potential
strategies for developing novel therapies. The identication
of rare but more penetrant variants associated with risk for
schizophrenia may provide an entry into addressing these
issues (72).
Fourth, the relationship of genetic lesions in synaptic pathways to other postulated etiologic/pathologic processes in
schizophrenia needs to be claried. In particular, altered
dopamine function, particularly in mesolimbic regions, has
been consistently implicated in playing a role in the disorder
and all currently known antipsychotic medications target this
system. While some genes associated with dopaminergic
function have been implicated in regions associated with
schizophrenia (e.g., COMT within the 22q11 deletion syndrome), it is not clear that it is deletion of COMT that is
responsible for increased susceptibility. This raises the question of how (or if) risk mediated through impacts on synaptic
function, particularly at glutamatergic synapses, is related to
dysregulation of dopamine signaling and the emergence of
psychotic symptoms. Both plasticity at glutamatergic synapses and dopamine play a central and coordinated role in
associative learning and prediction error signaling (7577).
Within this framework, changes in dopamine receptor activation can be considered intimately linked with the learning
process and the signaling of prediction errors (77,78). Altered
synaptic function may interfere with the delity of this process
and lead to the abnormalities in dopamine signaling that have
been linked to the development of psychotic symptoms (79).
Additionally, altered function at NMDA receptor synapses may
also have a particular impact on the regulation of interneuronal
function and the balance of excitation and inhibition in cortical
circuits, again potentially leading to a disinhibition of the
control of dopamine release (80,81). The exact links between
genetic risk factors at the synapse and alterations in dopamine
function remain to be determined, and it will be revealing to
investigate these processes in models of high-penetrance
genetic risk factors with high construct validity. Such models
may also be helpful in determining how validated environmental risk factors, such as early stress and cannabis use,
interact with genetic risk (71,79,82).
Finally, the emergent properties of genetic risk need to be
claried not only in cellular and animal model systems but also
in the context of the human brain and patient populations. The
delineation of potential pathologic processes helps focus
functional investigations of genetic risk in human carriers.
For example, alterations in NMDA receptor function may be
predicted to affect the overall balance of cortical excitation
and inhibition, with associated signal changes in electroencephalography/magnetoencephalography (83). Studying
such biological markers, even in rare individuals with penetrant
risk factors, may help, along with genetic investigation, to
demarcate signatures of specic risk pathways, which may

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provide a route to effective patient stratication and the better


targeting of both existing and novel therapeutics.

CONCLUSIONS
Genetic research into schizophrenia is at last beginning to
reveal coherent biological pathways implicated in the etiology
of the disorder. Recent studies of de novo and rare variants in
particular point to pathways involved in the regulation of the
synapse and synaptic plasticity in the pathogenesis of schizophrenia. It is highly unlikely that this will represent the only set
of molecular pathways implicated in the disorder, but the
identication of at least one system involved in risk for
schizophrenia paves the way for more detailed mechanistic
studies and potentially to stratied and novel therapeutic
approaches. Major challenges, however, remain ahead in
terms of understanding how genetic risk translates to biological risk and how different forms of risk, including environmental risk factors, converge to lead to the development of
symptoms. Furthermore, as it is increasingly apparent that the
symptoms of schizophrenia can arise from multiple genetic
(and environmental) insults, overlapping with risk for related
disorders such as ASD and ID, new approaches to stratify
patients for investigation and treatment will be required.

ACKNOWLEDGMENTS AND DISCLOSURES


This work was supported by a Wellcome Trust Strategic
Award (503147), Medical Research Council Centre grant
(G0801418), and Medical Research Council Programme grant
(G0800509).
We acknowledge Professor Adrian Harwood for helpful
comments.
The authors do not report any biomedical nancial interests
or potential conicts of interest.

ARTICLE INFORMATION
From the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (JH, MCO, MJO); Neuroscience
and Mental Health Research Institute (JH, ST, KLT, MJO), and
Cardiff School of Biosciences, Cardiff University, Cardiff,
United Kingdom (KLT).
Address correspondence to Jeremy Hall, M.B., Ph.D.,
Cardiff University, Neuroscience and Mental Health Research
Institute, Hadyn Ellis Building, Maindy Road, Cardiff, CF24
4HQ, United Kingdom; E-mail: HallJ10@cardiff.ac.uk.
Received Feb 6, 2014; revised Jun 16, 2014; accepted Jul
1, 2014.

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