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Biological
Psychiatry
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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Psychiatry
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).
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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.
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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