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European Neuropsychopharmacology (2015) 25, 671681

www.elsevier.com/locate/euroneuro

The current and potential impact of genetics


and genomics on neuropsychopharmacology
Paul J. Harrisonn
Department of Psychiatry, University of Oxford, Oxford OX3 7JX, United Kingdom
Received 19 July 2012; received in revised form 30 January 2013; accepted 22 February 2013

1.

KEYWORDS

Abstract

Antipsychotic;
Drug response;
Neuroleptic;
Pharmacogenetics;
Pharmacogenomics;
Schizophrenia;
Tolcapone

One justication for the major scientic and nancial investments in genetic and genomic
studies in medicine is their therapeutic potential, both for revealing novel targets for drugs
which treat the disease process, as well as allowing for more effective and safe use of existing
medications. This review considers the extent to which this promise has yet been realised
within psychopharmacology, how things are likely to develop in the foreseeable future, and the
key issues involved. It draws primarily on examples from schizophrenia and its treatments. One
observation is that there is evidence for a range of genetic inuences on different aspects of
psychopharmacology in terms of discovery science, but far less evidence that meets the
standards required before such discoveries impact upon clinical practice. One reason is that
results reveal complex genetic inuences that are hard to replicate and usually of very small
effect. Similarly, the slow progress being made in revealing the genes that underlie the major
psychiatric syndromes hampers attempts to apply the ndings to identify novel drug targets.
Nevertheless, there are some intriguing positive ndings of various kinds, and clear potential
for genetics and genomics to play an increasing and major role in psychiatric drug discovery.
& 2013 Elsevier B.V. and ECNP. All rights reserved.

Introduction

considers the extent to which genetic discoveries have


already made a difference to neuropsychopharmacology,
and the extent to which they are likely to do so in the
next few years. It focuses primarily on current and future
drugs for the treatment of schizophrenia, but the principles,
problems, and potential which it illustrates apply broadly
across neuropsychopharmacology (Malhotra et al., 2012b).
Before proceeding, two prefatory comments are worth
making. The rst concerns the methods used to nd the genetic
contributions to drug effects. These have paralleled the
approaches taken to nding genes contributing to diseases
and other phenotypes. Until recently, most studies were
candidate gene or pharmacogenetic in nature, whereby
one (or a few) genes, selected on the basis of a plausible
relationship to the target or metabolism of the drug were

Neuropsychopharmacology continues to search for new and


improved treatments for psychiatric disorders, as well as to
make more effective and safe use of current medications. It
is widely hoped, and often assumed, that genetic information can contribute in both respects, taking advantage of
the remarkable technological progress of the past decade.
Indeed, one justication and rationale for the massive
investments in psychiatric genetics has been the hope that
the ndings will lead to therapeutic benets. This review
n

Corresponding author.
E-mail address: paul.harrison@psych.ox.ac.uk

0924-977X/$ - see front matter & 2013 Elsevier B.V. and ECNP. All rights reserved.
http://dx.doi.org/10.1016/j.euroneuro.2013.02.005

672

P.J. Harrison

investigated to identify allelic variants (mostly single nucleotide


polymorphisms [SNPs]) which showed genetic association (i.e. a
statistical over-representation) in one group compared to
another (e.g. responders vs. non-responders). Whilst the candidate gene approach has produced a wealth of data, and
continues to be employed, it has largely been supplanted by
pharmacogenomic (i.e. genome-wide) association studies
(GWAS), in which hundreds of thousands of SNPs across the
genome are assayed simultaneously (Kingsmore et al., 2008;
Daly, 2010). The main advantage of a genomics rather than a
genetics approach is that the search is unbiased, and not
limited to candidate genes. However, because of the large
number of statistical tests performed in a GWAS, and the need
to control for multiple testing, very large samples (many
thousands) are required in order to have sufcient power. To
date, only a few pharmacogenomic GWAS have been reported,
and all have been much smaller than this. The second comment
is that, in addition to SNPs, an important source of genetic
variation arises from copy number variants (CNVs, also known as
structural variants), in which a length of DNA (from hundreds to
millions of nucleotides) is either deleted or duplicated. Major
psychiatric disorders, especially schizophrenia and autism, are
associated with an increased frequency of CNVs at several
genomic loci (Malhotra and Sebat, 2012). Any given CNV is very
rare but, if present, can represent a major risk factor. There
may also be similar rare but penetrant pharmacogenetic effects
of CNVs (e.g., a CNV which involves the dopamine D2 receptor
might affect response to antipsychotics), but these have not yet
been investigated; as such, this review only considers SNPs.

2. Genetic predictors of efcacy or


side-effects of current psychotropic drugs
Genetic factors can affect pharmacodynamics or pharmacokinetics; the former concerns allelic variation in the target of the

drug (e.g. receptor, transporter), whereas the latter primarily


refers to the cytochrome P450 (CYP) enzymes which metabolise
most drugs. It is worth noting however that this does not
translate simply into genotype-associated efcacy differences
being due to pharmacodynamics factors, and side-effects
to pharmacokinetic ones. For example, a drug causing many
side-effects (due to slow metabolism and thence high plasma
levels) may lead to poor compliance, and thence apparent
low efcacy.

2.1. Pharmacogenetics and pharmacogenomics of


antipsychotic response
Taking antipsychotics as an example, there have been many
hundreds of pharmacogenetic studies relating genotype to
their effects and side-effects. Initial enthusiasm was stimulated by Arranz et al., who showed that SNPs in HTR2A (the 5HT2A receptor) and in several other neurotransmitter receptor
genes helped predict response to clozapine (Arranz et al.,
1995, 2000). However, the many subsequent studies lead to a
more sanguine interpretation: a large number of isolated
positive ndings, a moderate number of studies with at least
one independent replication, and a very small number which
have been consistently replicated and/or are signicant by
meta-analysis. This applies both to therapeutic response (see
Arranz et al., 2011 for a comprehensive recent review and
discussion) and to the common side-effects (Table 1).
The antipsychotic literature also illustrates the fact that,
to date, pharmacogenomic studies are limited in number
and size. The most notable GWAS are in a subgroup of
subjects from the CATIE trial, with positive (or equivocally
positive) results regarding SNP correlates of treatment
response (McClay et al., 2011), and of metabolic (Adkins
et al., 2011) and movement-related (Aberg et al., 2010)
adverse effects; the positive GWAS results do not include

Table 1 Genetic associations of selected antipsychotic side-effects: replicated ndings from case-control studies, and
positive ndings from GWAS.
Phenotype, gene, and SNP

42 positive reports?

Meta-analysis?

GWAS-positive?

Overall evidence

Weight gain
ADRA2A-1291C/G
GNB3 rs5443
HTR2A 267C/T
HTR2C 759C/T
Leptin 2548A/G
MC4R rs489693
MEIS2 rs1568679

Yes
Yes
Yes
Yes
Yes
No
No

N/A
Trend
N/A
Positive
N/A
N/A
N/A

No
No
No
No
No
Yes
Yes

+
++
+
+++
++
+++
++

Agranulocytosis
HLA-DRB1
HLA-DRB5
HLA-DQB1

Yes
Yes
Yes

N/A
N/A
N/A

No
No
No

+
+
++

Tardive dyskinesia
COMT rs4680 158V/M
CYP2D6
D2R/ANKK1 rs1800497
MnSOD rs4880 9A/V

Yes
Yes
Yes
Yes

Positive
Mixed
N/A
Mixed

No
No
No
No

++
+
+
+

The table is based on results presented or summarised in Adkins et al. (2011), Arranz et al. (2011), Arranz and Munro (2011), Lett et al.
(2012), Malhotra et al. (2012a) and Risselda et al. (2011), N/A, not available. Overall evidence is a subjective interpretation of the
available data, on a + to ++++ scale.

The current and potential impact of genetics and genomics on neuropsychopharmacology

673

any of the robust ndings from the pharmacogenetic


studies. The antidepressant pharmacogenetic (Taylor
et al., 2010; Kato and Serretti, 2010) and pharmacogenomic
(Ising et al., 2009; Uher et al., 2010) literature is in a similar
position, in terms of its limitations and the conclusions
which can be drawn.

2.2. A qualitative pharmacogenetic interaction:


COMT genotype determines the cognitive response
to COMT inhibition
Like virtually all pharmacogenetic ndings, the examples
discussed above and illustrated in Table 1 concern SNPs
which affect the probability or the magnitude of a response
to, or side-effects from, a drug. However, the most interesting and powerful pharmacogenetic interaction is one
where a genetic factor determines the direction of effect of
a drug. To our knowledge, the only clear example of this
kind within neuropsychopharmacology comes from our
recent study of tolcapone, a brain-penetrant inhibitor of
the cortical dopamine-metabolising enzyme catechol-omethyl transferase (COMT) (Farrell et al., 2012).
Tolcapone is used in the adjunctive treatment of Parkinsons disease and is also under investigation in schizophrenia
and a range of other dopamine-related disorders. COMT
contains a common, functional, and well-studied SNP,
Val158Met (rs4680), which affects activity of the enzyme
(Chen et al., 2004), and thence impacts on performance and
neural activity during a range of behaviours in which
cortical dopamine participates, notably working memory
(Egan et al., 2001; Tunbridge et al., 2006; Mier et al., 2010).
The effects of COMT genotype and inhibition can be tted in
with the inverted U model, whereby optimal working
memory performance requires moderate levels of dopamine
signalling (Cools, DEsposito, 2011). That is, on tolcapone,
all people will move to the right on the curve (since COMT
inhibition increases dopamine availability), but those with
the COMT Val158 genotype will start off to the left of those
who are COMT Met158 (because of the higher activity of
COMT Val and thence higher dopamine catabolism). It may
thus be predicted that tolcapone will have a differential
effect depending on genotype: it may improve performance
in COMT Val158 subjects (by moving them closer to the peak
of the inverted U) but impair it in COMT Met158 Met subjects
(by moving them beyond the peak) (Figure 1). This is exactly
what Farrell et al. found, in a randomised double blind
study of a single dose of tolcapone, or placebo, given to
healthy young men: there was a genotype difference in
working memory performance (using the N-back task) on
placebo, with COMT Met158 subjects out-performing COMT
Val158 subjects, but after tolcapone this difference was
reversed such that COMT Val158 subjects did better than
COMT Met158 subjects. Prior studies had hinted at a similar
phenomenon but had not shown such a marked or statistically robust effect (Apud et al., 2007; Giakoumaki et al.,
2008). Farrell et al. (2012) also found an interactive
effect on risky decision-making in a gambling task: Met158
subjects were more cautious than Val158 subjects, but
this difference was reversed by tolcapone; this result
was somewhat unexpected, but is consistent with other
evidence that COMT participates in reward processing

Figure 1 The inverted U of cortical dopamine function. The


model provides a basis for predicting that the effects of COMT
inhibition will depend on COMT Val158Met genotype. Subjects
with COMT-Val genotype (triangles) have greater COMT activity
and thence lower cortical dopamine than do COMT-Met subjects
(circles). COMT inhibition with tolcapone increases dopamine
function and moves all subjects to the right, but the effect of
this may differ depending on genotype. As shown here,
compared to baseline or placebo, tolcapone moves COMT-Val
subjects closer to the peak, whereas COMT-Met subjects move
beyond it. However, different combinations of outcomes may
occur, depending on the persons starting position on the curve,
and how far to the right they are moved by the drug. Both
variables may in turn be affected by other genetic, epigenetic
or contextual factors, and by the particular behaviour or other
phenotype being measured. Here, the y-axis represents working
memory performance, or risk aversion, reecting the data of
Farrell et al. (2012).

(Tunbridge et al., 2012). Clearly, the ndings need to be


replicated and extended, but they serve as a striking
example of a true pharmacogenetic interaction. If genotype
had not been measured, it would have been concluded that
the drug was ineffective, since the opposing effects in the
two genotype groups would have cancelled out. The results
also suggest that in clinical practice, Val158Met genotype
may be a critical determinant of cognitive and behavioural
responses to COMT inhibition. Simplistically, tolcapone
might be benecial to COMT Val158 homozygotes but detrimental to COMT Met158 Met homozygotes (with heterozygotes likely to be intermediate). Certainly, future clinical
trials of these drugs should include COMT genotyping as an
integral part of their design.
The question arises as to why Farrell et al. (2012)
obtained such an unusually clear and large drug-bygenotype interaction. There are probably several reasons.
Primarily, it reects a fortunate combination of circumstances: that is, the functionality of COMT is known (viz., it
metabolises catechols), as is that of the Val158Met polymorphism (viz., it inuences enzyme activity); the drug
effectively and selectively targets the encoded protein; and
the predicted effects are grounded in a well-established
systems-level model (viz., the inverted U). Such
pharmacogenetically-favorable conditions are rare, if not

674
unique. In addition, the fact we only studied homozygotes
(to enhance the genetic effect), and selected a homogeneous (in terms of age and intelligence) group of young men
may have reduced the scope for age- and gender-related
variation in COMT function (Harrison and Tunbridge, 2008).

3. From interesting discoveries to clinical


utility
There is a marked discrepancy between the large number of
positive pharmacogenetic results in the literature, and the
lack of impact which they have had on current clinical
practice. Currently, there are a few psychotropic drugs for
which the FDA suggests CYP genotyping to help predict
dosing (see http://www.fda.gov/drugs/scienceresearch/
researchareas/pharmacogenetics/ucm083378.htm;
also
Swen et al., 2011). However, none have become incorporated into routine practice, and debate as to the appropriateness of such testing continues. This is exemplied by
debates about CYP genotyping and antidepressant use
(Black et al., 2007; Evaluation of Genomic Applications in
Practice and Prevention (EGAPP) Working Group, 2007).
Similarly, whilst there are several commercially available
kits for CYP and HLA genotype-based prediction of antipsy
chotic side-effects (Arranz and Munro, 2011), none are, to
my knowledge, in widespread use.
This lack of penetration of pharmacogenetic ndings into
clinical practice has several explanations. First, and critically, most positive ndings are not sufciently robust, or
lack prospective validation. Second, the size and quality of
many of the studies, and thence of the evidence that they
provide, is limited. For example, lack of blinding, heterogeneity of participants, use of other medications, variable
or poorly specied outcome measures, and lack of measures
of compliance. Third, even if statistically well founded, the
positive and negative predictive value of a genetic result is
either small or unknown. Fourth, the testing would need to
meet rigorous standards of quality control. Fifth, the costeffectiveness of genotyping in psychiatric practice has yet
to be demonstrated. Sixth, Black et al. (2007) draw attention to the fact that many clinicians may feel incompetent
to interpret genotyping results and thus reluctant to use
tests even when available. These authors also claim that the
greatest barrier to the use of genotyping (of CYP variants
for antidepressant response) is that many pharmaceutical
houses minimise the usefulness of this information in
selection of patients who would benet from their medications. This may or may not be true, but I suspect that any
rationale for doing so is increasingly offset by the potential
benets of being able to demonstrate greater efcacy,
safety, or cost-effectiveness, in a subgroup of patients, via
stratication in clinical trials and the move towards personalised medicines (Holsboer, 2008; Grecco et al., 2012;
McMahon and Insel, 2012).
The concept of the Number Needed to Screen (NNS)
may be valuable when thinking about clinical utility.
Analogous to the Number Needed to Treat (NNT), it is a
measure of how many people need to be tested (in this
context, genotyped) for one person to have their outcome
(in this context, treatment response) altered (Rembold,
1998). The smaller the number, the greater the value of the

P.J. Harrison
test. Formally, the NNS is the reciprocal of the absolute
change in the likelihood of the outcome as a result of the
test. It reects both the frequency of the marker being
tested (i.e. genotype) as well as the size of its effect.
As noted by McMahon and Insel (2012), different NNS may be
appropriate in different situations. For example, a relatively high NNS may still be valuable if it relates to a severe
adverse event (e.g. agranulocytosis), whereas a much lower
NNS would be needed to be useful when choosing between
two otherwise comparable treatments. Consideration of the
appropriate NNS could be factored into the further
discussion which is required as to the criteria to be adopted
when deciding when and how to introduce a pharmacogenetic test into clinical practice (and into clinical trials;
Relling and Klein, 2011), as well as on how to monitor the
tests implementation and impact (Khoury et al., 2010).
Thought also needs to be given on how to educate clinicians
in genomics (Winner et al., 2010), and in how to use such
information to guide actuarial decision-making (Khoury
et al., 2010).

4. Using genetics to inform and discover


novel drug targets
In the longer term, the real potential of genetics and
genomics in neuropsychopharmacology is to facilitate the
discovery of new drug targets and thence treatments. In the
work to date, a distinction can be made between targets
which were already of interest before genetic data emerged
which supported their candidacy, and those targets which
emerged specically because of genetic ndings, having not
previously been considered as such.

4.1.

Genetics and prior therapeutic candidates

For a number of potential drug targets in schizophrenia,


especially those modulating glutamatergic neurotransmission, evidence has emerged which suggests that the encoding gene may also be a susceptibility gene for the disorder.
Millan et al. (2012) reviewed medications under investigation for the treatment of cognitive impairment in schizophrenia and other psychiatric disorders. They list 34 such
drugs; for 8 of their targets (shown here in Table 2), there is
at least some evidence of genetic involvement in schizophrenia. In each case, there was a prior neurobiological or
pharmacological rationale to their investigation, which was
then supplemented by the genetic evidence. For example,
group II metabotropic glutamate receptors (mGlu2/3,
encoded by GRM2 and GRM3) were of therapeutic interest
given preclinical data showing that mGlu2/3 agonists
reversed cognitive impairments in NMDA receptor antagonist models of schizophrenia; evidence then emerged that
GRM3 may be a risk gene for schizophrenia (see Harrison
et al., 2008). Similarly, as noted earlier, COMT inhibitors
were already marketed for Parkinsons disease when the
signicance of the COMT Val158Met polymorphism for cortical dopamine and potentially for schizophrenia and its
treatment, was appreciated. As a nal example, D-amino
acid oxidase (DAO) inhibitors are in preclinical development, based in part on the role of DAO in metabolising the
NMDA receptor co-agonist D-serine, but also because of

The current and potential impact of genetics and genomics on neuropsychopharmacology

675

Table 2 Drug targets under investigation for cognitive improvement in schizophrenia for which genetic evidence to the
disorder has emerged.
Gene

Description/therapeutic rationale

DAO
GRM3

Metabolises D-serine, an NMDAR co-agonist


Inhibitory glutamate autoreceptor, modulates NMDAR
function
COMT
Metabolises cortical dopamine
CHRNA7 Nicotinic receptor, a7 subunit
DRD3
Dopamine D3 receptor
PDE4D Phosphodiesterase 4D
GSK3b Glycogen synthase kinase 3b
PPP3CC Protein phosphatase 2B (calcineurin)

Type of
drug

Linkage to
schizophrenia

Association to
schizophrenia

Inhibitor
Agonist

+
+

++
++

Inhibitor
+++
Agonist
++
Antagonist +
Inhibitor
+
Inhibitor
+
Inhibitor
++

+
+
++
+
++
++

Linkage: evidence that the gene locus shows linkage to schizophrenia. Association: evidence for genetic association to schizophrenia.
Ratings are a subjective interpretation of the evidence, on a + to ++++ scale.

evidence that DAO, and an interacting gene called DAOA,


may be risk genes for schizophrenia (Verrall et al., 2010).
Whilst genetic evidence is often adduced to support the
therapeutic candidacy of a drug target, its signicance can
be debated. Firstly, since the prior therapeutic interest may
have contributed to the gene being studied for disease
association in the rst place (i.e. as a candidate gene),
hence there is a degree of circularity to the argument, and
an increased risk of a false positive genetic nding. In any
event, the evidence for association to schizophrenia for the
genes listed in Table 2 is moderate, with only DAO showing
reasonable replication and/or nominal signicance in metaanalyses (Allen et al., 2008; Shi et al., 2008), and none of
the genes have been highlighted in GWAS studies. Also, the
extent to which being a risk gene strengthens the case for
being a therapeutic target per se ultimately depends on the
overall contribution which the gene plays in the disorder,
and the way in which the genetic variant alters its function
(see below). For example, in the case of DAO inhibitors, it is
the fact that DAO expression and enzyme activity are
increased in schizophrenia (Verrall et al., 2007; Madeira
et al., 2008; Burnet et al., 2008) which provide a stronger
rationale for their use than is any genetic association with
the illness.

4.2. Genetics and the discovery of novel


therapeutic targets
The other group of genetically-informed drug targets are
those which originate from genetic ndings, having not
previously been considered as such. For schizophrenia,
these include genes identied from candidate gene and
related approaches (e.g. neuregulin 1 [NRG1], dysbindin
[DTNBP1], and disrupted-in-schizophrenia-1 [DISC1]), as
well as those identied from GWAS; in the case of schizophrenia the latter include a range of novel genes, such as
ZNF804A, TCF4, and MIR137 (Mowry and Gratton, 2013).
Whilst there is great intellectual and conceptual attractiveness in viewing bona de risk genes as therapeutic targets,
there are several factors which temper enthusiasm. Table 3
summarises some of the key questions to be addressed. For
the following discussion, ZNF804A, the rst gene to be

Table 3 Key questions to address when determining


the therapeutic candidacy of a risk gene.
How strong is the evidence implicating the gene in the
disorder?
How big is the effect of the variant on disease risk?
What is known about the gene product, in terms of the
location and timing of its expression, and its functions?
Does the risk variant lead to known functional
differences from the non-risk form of the gene?

genome-wide signicant for schizophrenia (ODonovan


et al., 2008), is used as the main exemplar.
The rst constraint is that virtually all the statistically
robust risk SNPs for schizophrenia are non-coding (i.e. they
do not affect the amino-acid sequence of the encoded
protein) and have no known functional effects, nor a high
prior probability that they will prove to be functional; they
are silent polymorphisms. SNPs in this category therefore
lack the immediate therapeutic relevance of SNPs which
do affect the protein sequence and thence function (like
COMT Val158Met). For ZNF804A, the schizophrenia risk SNP
(rs1344706) comes into the non-coding or silent category,
since it is in an intron (a non-coding part of the gene). That
is not to say that silent SNPs are not worth pursuing.
A non-coding SNP can be functional by altering how the gene
is expressed, or it may be a surrogate for another variant
(the two SNPs being said to be in linkage disequilibrium)
which was not measured but which is a coding variant.
Expression can be altered in various ways by a non-coding
SNP. For example, by affecting splicing, such that a different mRNA and thence protein isoform is produced (e.g. by
retention or omission of an exon). This isoform can then
differ functionally from that of the canonical isoform.
KCNH2 provides a notable example of this kind. KCNH2
encodes the hERG1 potassium channel, which is important
in the heart for the QTc interval. Huffaker et al. (2009)
showed that a non-coding SNP within KCNH2 (rs1036145)
was associated with schizophrenia and affected expression
of a novel mRNA isoform, called KCNH2-3.1. This transcript
was markedly up-regulated in schizophrenia brain (whereas

676
other KCNH2 transcripts were not) and shown to encode a
protein with distinct electrophysiological properties which
they speculated might contribute to disorganised neuronal
ring in schizophrenia. They further suggested that a
selective inhibitor of KCNH2-3.1 could restore normal
potassium conductance kinetics in schizophrenia and thence
be an effective treatmentand free of the cardiac sideeffects which a drug acting on all forms of hERG1 would be
likely to have. Whilst this prediction remains to be tested, it
is of interest that rs1036145 has now been shown to affect
therapeutic response to existing antipsychotics (Apud et al.,
2012). Other examples where genetically-inuenced expression of specic isoforms may be therapeutically relevant
include an exon-skipping variant of GRM3 (Sartorius et al.,
2006, 2008), and the short and long isoforms of DRD2 (Barrie
et al., 2012).
A second issue is that all the known psychosis-associated
SNPs confer only a small increase in disease risk, usually
with an odds ratio of less than 1.2, meaning that the overall
functional impact (or therapeutic potential) of any given
SNP is correspondingly modest. Thus, the impact of a drug
correcting whatever effect the risk allele of rs1344706 (odds
ratio 1.1; Williams et al., 2011) might have on ZNF804A
function is not obvious. On the other hand, there are
examples from diabetes and psoriasis where drugs which
target genes of similarly small effect have proven to have
efcacy, so there is some room for optimism (Muglia, 2012).
Thirdly, the function of the encoded protein is itself often
unknown or, if known, does not seem likely to be a tractable
therapeutic target. ZNF804A also illustrates this point. Its
name comes from its zinc nger protein motif suggesting
that it belongs to this family of transcription factors (genes
encoding proteins which bind to DNA and regulate expression of other genes). However, little direct information is
available, for example, as to the genes which it regulates
(Girgenti et al., 2012; Hill et al., 2012) and the biological
consequences of allelic variation in rs1344706 (Hill and Bray,
2011). Moreover, if ZNF804A is indeed a transcription factor,
it is difcult to predict the consequences of pharmacologically modifying its actions (because it has so many downstream effects), and it may not be a readily druggable
target anyway (Hopkins and Groom, 2002) since it is likely to
act primarily in the nucleus and during development. Likewise, therapeutic targeting of MIR137, a microRNA would be
a substantial challenge since microRNAs do not encode a
protein product, but are small intracellular molecules which
are functional in their own right.
Fourthly, as noted earlier, in addition to common SNPs of
small effect, there are also CNVs which are risk factors for
psychosis conferring much higher odds ratios (typically 6 or
more; Mowry and Gratton, 2013). As such, correction of
whatever deleterious consequence the CNV causes would
seem more likely to be benecial, but this type of genetic
target has its own therapeutic limitations. The rarity of any
given CNV means that there would be very few patients with
the abnormality; on the other hand, if the CNV reveals a
gene which is in fact important more broadly in patients
with the disorder, then any therapeutic benets might also
generalise (Talkowksi et al., 2012). Also, many CNVs disrupt
multiple genes and so it is not clear what the therapeutic
target(s) would be. One notable exception is the VIPR2
locus, duplication of which is associated with schizophrenia

P.J. Harrison
(Vacic et al., 2011). VIPR2 encodes the vasoactive intestinal
peptide 2 receptor (VPAC2) which activates cAMP, and
represents a plausible therapeutic target, not least since
drugs acting on the receptor have already been developed
for a range of disorders (Groneberg et al., 2006).

4.3. Genetic interactions, pathways and


therapeutics
One way forward, which overcomes at least some of the
difculties outlined above, is to take a pathway- rather than
a gene-based approach. That is, to use genetics to dissect
out pathways and then view any component within the
pathway as a potential drug target (Wang et al., 2010). This
has several advantages. One is that different genes within a
biochemical pathway may each be small risk factors but
cumulatively the net effect is a more signicant functional
abnormality; another is that different genes may converge
on the same pathway, and therefore greater therapeutic
purchase is gained by a more downstream target; nally,
one component of a pathway, even if not a risk gene itself,
may be a better drug target than are any of the risk genes
themselves. Similar principles apply to genes which interact
with each other, either at the genetic level (epistasis) or
biologically, at the protein level. For example, DISC1
interacts with phosphodiesterases PDE4B and PDE4D (Millar
et al., 2005), with glycogen synthase kinase 3 (Ming and
Song, 2009), and with serine racemase (Ma et al., 2012); all
three of these enzymes represent more immediately tractable therapeutic targets than DISC1 itself (Soares et al.,
2011).
A good example of the neuropsychopharmacological
potential of the pathway-based approach concerns NRG1
signalling. NRG1 is a growth factor which plays many key
roles in development and plasticity, both in the nervous
system and elsewhere (Harrison and Law, 2006; Mei and
Xiong, 2008). Following the study of Stefansson et al.
(2002), NRG1 has been repeatedly associated with schizophrenia (Li et al., 2006), albeit in terms of non-coding SNPs
with small odds ratios and with negative or equivocal GWAS
results. NRG1 function in terms of its impact on NMDA
receptor signalling  is also altered in schizophrenia (Hahn
et al., 2006). Based on these data, NRG1 is a potential
treatment target; however, the remarkably pleiotropic roles
of NRG1, including in cancer, complicate this. NRG1 signals
via the ErbB receptor tyrosine kinases, especially ErbB4,
which in turn couples to several intracellular pathways,
including phosphoinositide 3-kinase (PI3K), which subsequently impacts on Akt1 (Figure 2). Genetic associations
to schizophrenia have been reported for ErbB4 and Akt1
(Emamian et al., 2004) as well as to NRG1 itself, with
epistatic interactions between these genes (Nicodemus
et al., 2010). These data suggest that the cumulative effect
of multiple genetic hits may lead to dysfunction of the
NRG1 signalling pathway in schizophrenia and that this may
be a valuable therapeutic target. Law et al. (2012) recently
produced direct evidence in support of these suggestions.
In a series of studies using human brain and lymphoblasts,
they showed increased expression in schizophrenia of ErbB4
and the p110d isoform of the catalytic subunit of PI3K
(encoded by PIK3CD) and decreased levels of the product of

The current and potential impact of genetics and genomics on neuropsychopharmacology


NRG1*
ErbB4
CYT1*
PI3K
p110

p110

PIP3*

CYT2

SHC
P110*

MAPK

AKT1/PKB*

Figure 2 The NRG1 signalling pathway greatly simplied and


highlighting the aspects implicated in schizophrenia and its
treatment by the work of Law et al. (2007, 2012). NRG1 signals
predominantly via the ErbB4 receptor tyrosine kinase. ErbB4 is
expressed as ErbB4-CYT1 and ErbB4-CYT2 variants; these arise
from alternative splicing and are differentially coupled to
downstream effectors: both activate the mitogen-activated
protein kinase (SHC-MAPK) pathway, but only ErbB4-CYT1 has
a phosphoinositide 3-kinase (PI3K) binding site. Class 1A PI3Ks
consist of heterodimers, with a regulatory p85 subunit, and
a catalytic p110 subunit (Engelman et al., 2006). The latter
exists as three isoforms (p110a, p110b and p110d), encoded
by PIK3CA, PIK3C and PIK3D genes respectively. PI3K catalyses production of phosphatidyl-inositol 3,4,5 triphosphate
(PI(3,4,5,)P3 or PIP3). PIP3 in turn impacts on Akt1/protein
kinase B (PKB) and thence further downstream effects (Manning
and Cantley, 2007). Asterisks denote molecules implicated
genetically or biochemically in schizophrenia, as described in
the text.

PI3K catalysis, phosphotidylinositol-3,4,5 triphosphate


(PIP3). They then showed that a small molecule inhibitor
of p110d corrected behavioural and biochemical abnormalities in animal models of schizophrenia, and increased
phosphorylation of Akt1.
The work of Law et al. (2012) illustrates several points
relevant to the importance of genetics in neuropsychopharmacology and to the issues discussed above. First, it sought
to understand how non-coding SNPs could be pathogenic,
and showed that the risk SNPs in NRG1 (Law et al., 2006)
and ErbB4 (Law et al., 2007) affected expression of a
specic isoform of each gene. Second, this isoformspecicity led to pathway specicity (see Figure 2), in that
the affected ErbB4 isoform (ErbB4 CYT-1), but not the
unaffected isoform (ErbB4 CYT-2) couples to PI3K, whereas
both ErbB4 isoforms couple to other downstream pathways
(Mei and Xiong, 2008). Third, the isoform selectivity also
observed for p110 (with only p110d but not the other p110
isoforms being up-regulated in schizophrenia) provided the
chance for equally selective drug targeting (c.f. the preceding discussion; Barrie et al., 2012), reducing the chance
of toxicity or side-effects which a broader interference with

677

this ubiquitous signalling pathway could well produce.


Fourth, Law et al. did not just measure gene expression,
but gene function, by showing that the production of PIP3
by PI3K was decreased, thus providing a stronger therapeutic rationale. Finally, completing the circle, Law et al.
(2012) then sought and found preliminary evidence for
genetic association of PIK3CD to schizophrenia.
Clearly, much further work is required to establish
whether p110d inhibition is a viable and effective treatment
for schizophrenia, but the ndings provide an important
proof of principle showing how the careful genetic and
molecular dissection of a biochemical pathway can reveal a
novel potential drug target (Rico, 2012). The work was
stimulated by the genetic associations of NRG1 and ErbB4
with schizophrenia, and the subsequent efforts to explain
their biological basis provide a powerful illustration of how
genetics may contribute to therapeutic innovation in
neuropsychopharmacology.

5.

Conclusions

Genetics and genomics will undoubtedly continue to be an


integral part of neuropsychopharmacology in the coming
years, both in terms of identifying SNPs and other genetic
variants which can explain and predict individual differences in response to a drug (Lotrich, 2012), but also as a
driver for the target (and thence drug) discovery process
(De Leon, 2009). The examples given in this review are
testament to the many discoveries already made, and the
potential of the eld, in both respects. As such, it is
important for all psychiatrists to have some understanding
of genetics as part of their psychopharmacological knowledge (Winner et al., 2010; Harrison et al., 2011). Equally, it
remains the case that pharmacogenetic testing is not part of
routine clinical practice for any current psychotropic drugs,
since no nding yet meets the necessary criteria; most
ndings lack the necessary robustness or predictive value.
Neither has a genetic nding yet led directly to a psychotropic drug of proven clinical efcacy. As such, the promise
of genetics and genomics for neuropsychopharmacology
remains largely unrealised. Whether this situation changes
dramatically in the next few years is difcult to predict. The
continuing technical developments in next-generation
sequencing and computational analysis, coupled with
rapidly decreasing costs, will produce ever more complete
characterisation of the genome, as well as the epigenome,
transcriptome, proteome, and metabolome. Hidden
amongst these omes will lie the genetic basis for individual
differences in drug response, as well as the risk genes which
represent, simplistically at least, rational drug targets for a
disorder. However, these studies will also highlight the
extent of individual sequence variation within the genome
(e.g. estimates of 10,000 variants, including 200 proteininactivating mutations, per person; MacArthur et al., 2012).
Identifying the handful of variants which are pharmacogenomically signicant, in a clinical as well as a statistical
sense, will be a major experimental and bioinformatic
challenge (Nelson et al., 2012; Roberts et al., 2012).
Moreover, the genetic architecture of drug response remain
unknown; that is, we do not know how many genes or
genetic variants are there to be found which contribute

678
sufcient amounts of the variance to be clinically useful,
either as predictors of response, or to be considered effective
(and druggable) targets. These notes of caution are not
intended to diminish the importance of, nor enthusiasm for,
genetics and genomics as an essential component of neuropsychopharmacological research programs and trial designs.
They do, however, suggest that premature or exaggerated
claims as to the signicance of ndings, especially with regard
to their clinical therapeutic utility, should be avoided.

Role of the funding source


My groups work has been supported by various funders,
notably the Wellcome Trust, Medical Research Council, and
Stanley Medical Research Institute. None of these funders
had any role in the writing of this review or the decision to
submit it for publication.

Contributors
I was the author of this manuscript and take sole responsibility
for it.

Conict of interest
In the past three years, I have received honoraria for lectures from
AstraZeneca, Janssen, Otsuka and Takeda, for consulting from
Merck, and an unrestricted educational grant from Takeda. I have
acted as an expert witness in a pharmaceutical patent case.

Acknowledgement
I am grateful to the many current and past members of the group,
and our collaborators, whose ideas and ndings have shaped my
thoughts and the opinions expressed here. Particular thanks are due
to Elizabeth Tunbridge, Amanda Law and Daniel Weinberger.

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