The current and potential impact of genetics and genomics on neuropsychopharmacology

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Abstract

One justification for the major scientific and financial 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 influences 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 influences 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 findings to identify novel drug targets. Nevertheless, there are some intriguing positive findings of various kinds, and clear potential for genetics and genomics to play an increasing and major role in psychiatric drug discovery.

Introduction

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 justification and rationale for the massive investments in psychiatric genetics has been the hope that the findings will lead to therapeutic benefits. This review 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 first concerns the methods used to find the genetic contributions to drug effects. These have paralleled the approaches taken to finding 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 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 sufficient 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.

Section snippets

Genetic predictors of efficacy 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 efficacy differences being due to pharmacodynamics factors, and side-effects to pharmacokinetic ones. For example, a drug causing many side-effects

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

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 specifically because of genetic findings, having not previously been considered as such.

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 field, in both respects. As

Role of the funding source

My group's 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.

Conflict 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 findings have shaped my thoughts and the opinions expressed here. Particular thanks are due to Elizabeth Tunbridge, Amanda Law and Daniel Weinberger.

References (86)

  • B.D. Manning et al.

    AKT/PKB signalling: navigating downstream

    Cell

    (2007)
  • G.-I. Ming et al.

    DISC1 partners with GSK3 beta in neurogenesis

    Cell

    (2009)
  • J.J. Shi et al.

    Genetic associations with schizophrenia: meta-analyses of 12 candidate genes

    Schizophr. Res.

    (2008)
  • H. Stefansson et al.

    Neuregulin 1 and susceptibility to schizophrenia

    Am. J. Hum. Genet.

    (2002)
  • M.J. Taylor et al.

    Antidepressant response and the serotonin transporter gene-linked polymorphic region

    Biol. Psychiatry

    (2010)
  • E.M. Tunbridge et al.

    Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond

    Biol. Psychiatry

    (2006)
  • D.E. Adkins et al.

    Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs

    Mol. Psychiatry

    (2011)
  • N.C. Allen et al.

    Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database

    Nat. Genet.

    (2008)
  • J.A. Apud et al.

    Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia

    Am. J. Psychiatry

    (2012)
  • J.A. Apud et al.

    Tolcapone improves cognition and cortical information processing in normal human subjects

    Neuropsychopharmacology

    (2007)
  • M.J. Arranz et al.

    Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia

    Expert Rev. Clin. Pharmacol.

    (2011)
  • M.J. Arranz et al.

    Pharmacogenetics of response to antipsychotics in patients with schizophrenia

    CNS Drugs

    (2011)
  • E.S. Barrie et al.

    mRNA Transcript diversity creates new opportunities for pharmacological intervention

    Mol. Pharmacol.

    (2012)
  • J.L. Black et al.

    The impact of CYP allelic variation on antidepressant metabolism: a review

    Expert Opin. Drug Metab. Toxicol.

    (2007)
  • P.W.J. Burnet et al.

    d-amino acid oxidase activity and expression are increased in schizophrenia

    Mol. Psychiatry

    (2008)
  • R. Cools et al.

    Inverted-U-shaped dopamine actions on human working memory and cognitive control

    Biol. Psychiatry

    (2011)
  • A.K. Daly

    Genome-wide association studies in pharmacogenomics

    Nat. Rev. Genet.

    (2010)
  • J. De Leon

    Pharmacogenomics: the promise of personalized medicine for CNS disorders

    Neuropsychopharmacology

    (2009)
  • M.F. Egan et al.

    Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia

    Proc. Natl. Acad. Sci. USA

    (2001)
  • E.S. Emamian et al.

    Convergent evidence for impaired AKT1-GSK3beta signalling in schizophrenia

    Nat. Genet.

    (2004)
  • J.A. Engelman et al.

    The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

    Nat. Rev. Genet.

    (2006)
  • Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group

    Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

    Genet. Med

    (2007)
  • S.G. Giakoumaki et al.

    Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val(158)Met polymorphism

    Neuropsychopharmacology

    (2008)
  • M.J. Girgenti et al.

    ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2

    PLoS One

    (2012)
  • N. Grecco et al.

    PhRMA survey of pharmacogenomic and pharmacodynamics evaluations: what next?

    Clin. Pharmacol. Ther.

    (2012)
  • C.G. Hahn et al.

    Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia

    Nat. Med.

    (2006)
  • P.J. Harrison et al.

    Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders

    Neuropsychopharmacology

    (2008)
  • P.J. Harrison et al.

    The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia

    J. Psychopharmacol.

    (2008)
  • P.J. Harrison et al.

    No psychiatry without psychopharmacology

    Br. J. Psychiatry

    (2011)
  • M. Hill et al.

    Allelic differences in nuclear protein binding at a genome-wide significant risk variant for schizophrenia in ZNF804A

    Mol. Psychiatry

    (2011)
  • M.J. Hill et al.

    Knockdown of the psychosis susceptibility gene ZNF804A alters expression of genes involved in cell adhesion

    Hum. Mol. Genet.

    (2012)
  • F. Holsboer

    How can we realize the promise of personalized antidepressant medicines?

    Nat. Rev. Neurosci.

    (2008)
  • A.L. Hopkins et al.

    The druggable genome

    Nat. Rev. Drug Discovery

    (2002)
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