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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





5 authors, including:
Jeremy Hall

Simon Trent

Cardiff University

Cardiff University





Kerrie Thomas
Cardiff University

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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
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.
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.


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


& 2015 Society of Biological Psychiatry
Biological Psychiatry January, 2015; 77:5258


ISSN: 0006-3223


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).


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).


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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Genetic Risk for Schizophrenia

Figure 1. Converging synaptic pathways implicated in schizophrenia risk.

Genes enriched for de novo mutations
in schizophrenia or enriched for rare
disruptive mutations in cases relative to
control subjects were found to conPresynaptic
verge on common biological pathways:
the N-methyl-D-aspartate receptor
(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,
voltage-gated calcium channels (VGCCs),
and F-actin polymerization (7,30,31).
These ndings implicate interconnected biological mechanisms predoSynaptic receptor trafficking
minantly at the postsynaptic density
of glutamatergic synapses and their
role in regulating plasticity. Synaptic
activity triggers the entry of calcium
into the postsynaptic dendritic spines
directly through VGCCs and via glutamate-activated NMDA receptors,
resulting in the subsequent activation
of second messenger systems and an
increase in ARC messenger RNA
(mRNA) transcription (45,47). GlutaNucleus
matergic activation of metabotropic
glutamate receptor (mGluR)1/5 is
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-


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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Genetic Risk for Schizophrenia

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.


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
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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Genetic Risk for Schizophrenia

provide a route to effective patient stratication and the better

targeting of both existing and novel therapeutics.

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.


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

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:
Received Feb 6, 2014; revised Jun 16, 2014; accepted Jul
1, 2014.




Bray NJ, Owen MJ (2001): Searching for schizophrenia genes. Trends

Mol Med 7:169174.
Gottesman II, Shields J (1967): A polygenic theory of schizophrenia.
Proc Natl Acad Sci U S A 58:199205.
Insel TR (2009): Translating scientic opportunity into public health
impact: A strategic plan for research on mental illness. Arch Gen
Psychiatry 66:128133.
Doherty JL, ODonovan MC, Owen MJ (2012): Recent genomic
advances in schizophrenia. Clin Genet 81:103109.
Kim Y, Zerwas S, Trace SE, Sullivan PF (2011): Schizophrenia
genetics: Where next? Schizophr Bull 37:456463.




















Biological Psychiatry January, 2015; 77:5258

Mowry BJ, Gratten J (2013): The emerging spectrum of allelic variation

in schizophrenia: Current evidence and strategies for the identication
and functional characterization of common and rare variants. Mol
Psychiatry 18:3852.
Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D,
et al. (2012): De novo CNV analysis implicates specic abnormalities
of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 17:142153.
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al.
(2010): Functional impact of global rare copy number variation in
autism spectrum disorders. Nature 466:368372.
Kenny EM, Cormican P, Furlong S, Heron E, Kenny G, Fahey C, et al.
(2014): Excess of rare novel loss-of-function variants in synaptic
genes in schizophrenia and autism spectrum disorders. Mol Psychiatry 19:872879.
International Schizophrenia Consortium, Purcell SM, Wray NR, Stone
JL, Visscher PM, ODonovan MC, et al. (2009): Common polygenic
variation contributes to risk of schizophrenia and bipolar disorder.
Nature 460:748752.
Owen MJ, Craddock N, ODonovan MC (2010): Suggestion of roles for
both common and rare risk variants in genome-wide studies of
schizophrenia. Arch Gen Psychiatry 67:667673.
ODonovan MC, Craddock N, Norton N, Williams H, Peirce T,
Moskvina V, et al. (2008): Identication of loci associated with
schizophrenia by genome-wide association and follow-up. Nat Genet
Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Peer I, et al.
(2009): Common variants on chromosome 6p22.1 are associated with
schizophrenia. Nature 460:753757.
Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S,
Rujescu D, et al. (2009): Common variants conferring risk of schizophrenia. Nature 460:744747.
Williams HJ, Craddock N, Russo G, Hamshere ML, Moskvina V,
Dwyer S, et al. (2011): Most genome-wide signicant susceptibility
loci for schizophrenia and bipolar disorder reported to date crosstraditional diagnostic boundaries. Hum Mol Genet 20:387391.
International Schizophrenia Consortium (2008): Rare chromosomal
deletions and duplications increase risk of schizophrenia. Nature 455:
Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A,
Steinberg S, et al. (2008): Large recurrent microdeletions associated
with schizophrenia. Nature 455:232236.
Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans
P, et al. (2009): Support for the involvement of large copy number
variants in the pathogenesis of schizophrenia. Hum Mol Genet 18:
Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, et al.
(2004): Large-scale copy number polymorphism in the human
genome. Science 305:525528.
Rees E, Moskvina V, Owen MJ, ODonovan MC, Kirov G (2011): De
novo rates and selection of schizophrenia-associated copy number
variants. Biol Psychiatry 70:11091114.
Lee SH, DeCandia TR, Ripke S, Yang J, Schizophrenia Psychiatric
Genome-Wide Association Study Consortium, International Schizophrenia Consortium, et al. (2012): Estimating the proportion of
variation in susceptibility to schizophrenia captured by common
SNPs. Nat Genet 44:247250.
Rees E, Kirov G, ODonovan MC, Owen MJ (2012): De novo mutation
in schizophrenia. Schizophr Bull 38:377381.
Veltman JA, Brunner HG (2012): De novo mutations in human genetic
disease. Nat Rev Genet 13:565575.
Neale BM, Kou Y, Liu L, Maayan A, Samocha KE, Sabo A, et al.
(2012): Patterns and rates of exonic de novo mutations in autism
spectrum disorders. Nature 485:242245.
ORoak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al.
(2012): Sporadic autism exomes reveal a highly interconnected protein
network of de novo mutations. Nature 485:246250.
Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T,
et al. (2012): Range of genetic mutations associated with severe


Genetic Risk for Schizophrenia



















non-syndromic sporadic intellectual disability: An exome sequencing

study. Lancet 380:16741682.
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ,
Willsey AJ, et al. (2012): De novo mutations revealed by whole-exome
sequencing are strongly associated with autism. Nature 485:237241.
Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, et al.
(2011): Increased exonic de novo mutation rate in individuals with
schizophrenia. Nat Genet 43:860863.
Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, et al.
(2012): De novo gene mutations highlight patterns of genetic and
neural complexity in schizophrenia. Nat Genet 44:13651369.
Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S,
Gormley P, et al. (2014): De novo mutations in schizophrenia implicate
synaptic networks. Nature 506:179184.
Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P,
et al. (2014): A polygenic burden of rare disruptive mutations in
schizophrenia. Nature 506:185190.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB,
Cooper GM, et al. (2008): Rare structural variants disrupt multiple
genes in neurodevelopmental pathways in schizophrenia. Science
Emes RD, Pocklington AJ, Anderson CN, Bayes A, Collins MO,
Vickers CA, et al. (2008): Evolutionary expansion and anatomical
specialization of synapse proteome complexity. Nat Neurosci 11:
Bayes A, Grant SG (2009): Neuroproteomics: Understanding the
molecular organization and complexity of the brain. Nat Rev Neurosci
Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, et al.
(2008): The fragile X syndrome protein represses activitydependent translation through CYFIP1, a new 4E-BP. Cell 134:
Fernandez E, Rajan N, Bagni C (2013): The FMRP regulon: From
targets to disease convergence. Front Neurosci 7:191.
Cingolani LA, Goda Y (2008): Actin in action: The interplay between
the actin cytoskeleton and synaptic efcacy. Nat Rev Neurosci 9:
Casamassima F, Hay AC, Benedetti A, Lattanzi L, Cassano GB, Perlis
RH (2010): L-type calcium channels and psychiatric disorders:
A brief review. Am J Med Genet B Neuropsychiatr Genet 153B:
Schizophrenia Psychiatric Genome-Wide Association Study Consortium (2011): Genome-wide association study identies ve new
schizophrenia loci. Nat Genet 43:969976.
Bhat S, Dao DT, Terrillion CE, Arad M, Smith RJ, Soldatov NM, Gould
TD (2012): CACNA1C (Cav1.2) in the pathophysiology of psychiatric
disease. Prog Neurobiol 99:114.
Ripke S, ODushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S,
et al. (2013): Genome-wide association analysis identies 13 new risk
loci for schizophrenia. Nat Genet 45:11501159.
Moosmang S, Haider N, Klugbauer N, Adelsberger H, Langwieser N,
Muller J, et al. (2005): Role of hippocampal Cav1.2 Ca21 channels in
NMDA receptor-independent synaptic plasticity and spatial memory.
J Neurosci 25:98839892.
Rao VR, Finkbeiner S (2007): NMDA and AMPA receptors: Old
channels, new tricks. Trends Neurosci 30:284291.
Wang H, Hu Y, Tsien JZ (2006): Molecular and systems mechanisms
of memory consolidation and storage. Prog Neurobiol 79:123135.
Finkbeiner S, Greenberg ME (1998): Ca21 channel-regulated neuronal
gene expression. J Neurobiol 37:171189.
West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM,
Shaywitz AJ, et al. (2001): Calcium regulation of neuronal gene
expression. Proc Natl Acad Sci U S A 98:1102411031.
Steward O, Worley PF (2001): Selective targeting of newly synthesized
Arc mRNA to active synapses requires NMDA receptor activation.
Neuron 30:227240.
Vanhoutte P, Bading H (2003): Opposing roles of synaptic and
extrasynaptic NMDA receptors in neuronal calcium signalling and
BDNF gene regulation. Curr Opin Neurobiol 13:366371.


















Steward O, Wallace CS, Lyford GL, Worley PF (1998): Synaptic

activation causes the mRNA for the IEG Arc to localize selectively
near activated postsynaptic sites on dendrites. Neuron 21:741751.
Yin Y, Edelman GM, Vanderklish PW (2002): The brain-derived
neurotrophic factor enhances synthesis of Arc in synaptoneurosomes.
Proc Natl Acad Sci U S A 99:23682373.
Huang F, Chotiner JK, Steward O (2007): Actin polymerization and
ERK phosphorylation are required for Arc/Arg3.1 mRNA targeting to
activated synaptic sites on dendrites. J Neurosci 27:90549067.
Rodriguez JJ, Davies HA, Silva AT, De Souza IE, Peddie CJ, Colyer
FM, et al. (2005): Long-term potentiation in the rat dentate gyrus is
associated with enhanced Arc/Arg3.1 protein expression in spines,
dendrites and glia. Eur J Neurosci 21:23842396.
Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, et al.
(2010): The Arc of synaptic memory. Exp Brain Res 200:125140.
Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL,
Worley PF, Barnes CA (2000): Inhibition of activity-dependent arc
protein expression in the rat hippocampus impairs the maintenance of
long-term potentiation and the consolidation of long-term memory.
J Neurosci 20:39934001.
Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross
C, et al. (2006): Arc/Arg3.1 is essential for the consolidation of
synaptic plasticity and memories. Neuron 52:437444.
Messaoudi E, Kanhema T, Soule J, Tiron A, Dagyte G, da Silva B,
et al. (2007): Sustained Arc/Arg3.1 synthesis controls long-term
potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27:1044510455.
Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N,
et al. (2006): Arc/Arg3.1 interacts with the endocytic machinery to
regulate AMPA receptor trafcking. Neuron 52:445459.
Huganir RL, Nicoll RA (2013): AMPARs and synaptic plasticity: The
last 25 years. Neuron 80:704717.
Peebles CL, Yoo J, Thwin MT, Palop JJ, Noebels JL, Finkbeiner S
(2010): Arc regulates spine morphology and maintains network
stability in vivo. Proc Natl Acad Sci U S A 107:1817318178.
Rial Verde EM, Lee-Osbourne J, Worley PF, Malinow R, Cline HT (2006):
Increased expression of the immediate-early gene arc/arg3.1 reduces
AMPA receptor-mediated synaptic transmission. Neuron 52:461474.
Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, Halford JM, et al. (2006):
Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442:814817.
Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D,
et al. (2006): Arc/Arg3.1 mediates homeostatic synaptic scaling of
AMPA receptors. Neuron 52:475484.
Waung MW, Pfeiffer BE, Nosyreva ED, Ronesi JA, Huber KM (2008):
Rapid translation of Arc/Arg3.1 selectively mediates mGluRdependent LTD through persistent increases in AMPAR endocytosis
rate. Neuron 59:8497.
Korb E, Wilkinson CL, Delgado RN, Lovero KL, Finkbeiner S (2013):
Arc in the nucleus regulates PML-dependent GluA1 transcription and
homeostatic plasticity. Nat Neurosci 16:874883.
Routtenberg A (2013): Lifetime memories from persistently supple
synapses. Hippocampus 23:202206.
Catterall WA, Few AP (2008): Calcium channel regulation and
presynaptic plasticity. Neuron 59:882901.
Sudhof TC (2008): Neuroligins and neurexins link synaptic function to
cognitive disease. Nature 455:903911.
Sullivan PF, Daly MJ, ODonovan M (2012): Genetic architectures of
psychiatric disorders: The emerging picture and its implications. Nat
Rev Genet 13:537551.
de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes
T, et al. (2012): Diagnostic exome sequencing in persons with severe
intellectual disability. N Engl J Med 367:19211929.
Malhotra D, Sebat J (2012): CNVs: Harbingers of a rare variant
revolution in psychiatric genetics. Cell 148:12231241.
Craddock N, Owen MJ (2010): The Kraepelinian dichotomy going,
going... but still not gone. Br J Psychiatry 196:9295.
Owen MJ (2012): Implications of genetic ndings for understanding
schizophrenia. Schizophr Bull 38:904907.

Biological Psychiatry January, 2015; 77:5258



Genetic Risk for Schizophrenia







Ho VM, Lee JA, Martin KC (2011): The cell biology of synaptic

plasticity. Science 334:623628.
Nathan PJ, Cobb SR, Lu B, Bullmore ET, Davies CH (2011): Studying
synaptic plasticity in the human brain and opportunities for drug
discovery. Curr Opin Pharmacol 11:540548.
Corlett PR, Honey GD, Krystal JH, Fletcher PC (2011): Glutamatergic
model psychoses: Prediction error, learning, and inference. Neuropsychopharmacology 36:294315.
Glimcher PW (2011): Understanding dopamine and reinforcement
learning: The dopamine reward prediction error hypothesis. Proc Natl
Acad Sci U S A 108(suppl 3):1564715654.
Hall J, Romaniuk L, McIntosh AM, Steele JD, Johnstone EC, Lawrie
SM (2009): Associative learning and the genetics of schizophrenia.
Trends Neurosci 32:359365.
Schultz W, Dickinson A (2000): Neuronal coding of prediction errors.
Annu Rev Neurosci 23:473500.
Howes OD, Murray RM (2014): Schizophrenia: An integrated
sociodevelopmental-cognitive model. Lancet 383:16771687.






Biological Psychiatry January, 2015; 77:5258

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Lisman JE, Coyle JT, Green RW, Javitt DC, Benes FM, Heckers S,
Grace AA (2008): Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31:234242.
Lewis DA (2012): Cortical circuit dysfunction and cognitive decits in
schizophreniaimplications for preemptive interventions. Eur J Neurosci 35:18711878.
Brown AS (2011): The environment and susceptibility to schizophrenia. Prog Neurobiol 93:2358.
Gonzalez-Burgos G, Lewis DA (2012): NMDA receptor hypofunction,
parvalbumin-positive neurons, and cortical gamma oscillations in
schizophrenia. Schizophr Bull 38:950957.
Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, et al.
(2008): Elongation factor 2 and fragile X mental retardation protein
control the dynamic translation of Arc/Arg3.1 essential for mGluRLTD. Neuron 59:7083.
Shepherd JD, Bear MF (2011): New views of Arc, a master regulator of
synaptic plasticity. Nat Neurosci 14:279284.