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Evaluating Historical Candidate Genes for Schizophrenia

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Evaluating Historical Candidate Genes for Schizophrenia Molecular Psychiatry (2015) 20, 555–562 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp EXPERT REVIEW Evaluating historical candidate genes for schizophrenia MS Farrell1, T Werge2,3,4, P Sklar5,6,7, MJ Owen8,9, RA Ophoff10,11,12,MCO’Donovan8,9, A Corvin13, S Cichon14,15,16 and PF Sullivan1,17,18 Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. Molecular Psychiatry (2015) 20, 555–562; doi:10.1038/mp.2015.16; published online 10 March 2015 INTRODUCTION unreasonable to hope that similar studies might work for In this review, we consider the current status of candidate genes schizophrenia. Realization of this expectation proved difficult. A for schizophrenia that were prominent in the literature before the pattern emerged whereby an initial claim of association for a genome-wide association study (GWAS) era. This review was seemingly plausible, even exciting, candidate gene for schizo- invited by Professor Julio Licinio, the editor of Molecular Psychiatry. phrenia was followed by a mixed pattern of non-replications and 1 replication. Thus, candidate gene association studies for schizo- Owing to the high heritability of schizophrenia, there have 7–10 been many efforts to discover the causative genetic factors, and phrenia became controversial. candidate gene studies have been a major approach. For example, The goal of this review is to evaluate the current status of the SZGene database2 (obtained November 2009) listed 1406 historical candidate genes for schizophrenia. The motivation is candidate gene papers investigating over 700 genes. In these straightforward: there are hundreds of papers on these genes, several of these genes have motivated considerable biological studies, one or more genetic markers in genes hypothesized to be experimentation, and as recent large-scale studies have expanded involved in the etiology of schizophrenia were genotyped in cases our knowledge base, it is reasonable to review this topic. Early with schizophrenia and controls. Prior to the advances brought 3 candidate gene studies evaluated tens of genetic markers in about by the Human Genome Project and the International hundreds of subjects, and more recent studies conducted 4 fi HapMap Project, it was dif cult and expensive to genotype a genome-wide comparisons of millions of genetic markers in tens comprehensive list of genetic variants in a genomic region. of thousands of subjects. The largest published study is of 34 000 Investigators thus tended to genotype a few genetic markers in a cases from the Psychiatric Genomics Consortium (PGC), which candidate gene selected on the basis of prevailing theories of the identified 108 genome-wide significant loci.11 etiology of schizophrenia (for example, antipsychotic pharmacol- Almost all of these historical candidate gene studies evaluated ogy) or positional candidate genes from linkage or cytogenetic the role of common variation (one part of a spectrum of variants studies. involved in schizophrenia). Our evaluation includes: (a) meta- The candidate gene strategy had a few notable successes in analysis of candidate gene studies, (b) PGC schizophrenia mega- identifying genetic variation for other complex diseases. Influential analysis results,11 (c) expert evaluations from researchers on examples included replicated associations of Alzheimer’s disease specific candidate genes and (d) survey ratings from schizophrenia with common variation in APOE5 and alcohol dependence with genomics investigators. The latter two approaches are not common variants in alcohol metabolic genes.6 It was thus not ‘scientific’ in a strict sense, but rather provide a general guide to 1Center for Psychiatric Genomics, Department of Genetics, Genomic Medicine, University of North Carolina, Chapel Hill, NC, USA; 2Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Denmark; 3Department of Clinical Medicine, University of Copenhagen, Copenhagen, Aarhus, Denmark; 4The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; 5Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 8MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK; 9National Centre for Mental Health, Cardiff University, Cardiff, UK; 10Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA; 11Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 12Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; 13Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Ireland; 14Division of Medical Genetics, Department of Biomedicine, University Basel, Basel, Switzerland; 15Institute of Human Genetics, University of Bonn, Bonn, Germany; 16Department of Genomics, Life and Brain Center, Bonn, Germany; 17Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden and 18Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA. Correspondence: Dr PF Sullivan, Center for Psychiatric Genomics, Department of Genetics, CB#7264, 5097 Genomic Medicine, University of North Carolina, Chapel Hill 27599-7264, NC, USA. E-mail: [email protected] Received 6 August 2014; revised 14 November 2014; accepted 5 January 2015; published online 10 March 2015 Historical schizophrenia candidate genes evaluation MS Farrell et al 556 the ‘significance’ and ‘impact’ that the earlier findings currently firmest proponents of a particular candidate gene in schizo- have in the field. phrenia. These individuals were identified using PubMed searches: (gene (all fields) or 'protein name' (all fields)) and ('schizophrenia' (MeSH terms) or 'schizophrenia' (all fields)). Informed investigators MATERIALS AND METHODS were contacted to request their summary judgment of the current We selected 25 genes prominent in the pre-GWAS era. The first status of one particular gene as a genetic risk factor for schizophrenia GWAS appeared in 2007 but, given that many schizophrenia (1 = very unlikely and 5 = very likely). Genetic risk candidate gene association studies were published in 2008, we could refer to common, uncommon, rare, private or de novo evaluated candidate gene studies published in calendar year 2008 genetic variation. A draft of Table 2 was supplied upon request. or earlier. The 25 genes we selected were either featured in Informed investigators were given the opportunity to include text – reviews of the genetics of schizophrenia10,12 14 or were highly in the supplement to explain their rating. studied (⩾20 papers recorded in SZGene). The genes and the Fourth, we obtained perspectives from ‘schizophrenia geneti- rationale for being a candidate gene for schizophrenia are given in cists’. We used principal investigators from the PGC schizophrenia Table 1. We continued several important assumptions made by working group11 as a convenience sample. We obtained responses virtually all candidate gene studies (see limitations). First, these from 24 investigators for summary judgments using the same studies evaluated ‘schizophrenia’ as a dichotomous entity. Second, rating scheme as for the informed investigators. Many of these as with the primary studies, we assumed that genetic variants act investigators study common, uncommon, rare, private or de novo on the gene it was in or near. This assumption is crucial and will be genetic variation. inaccurate for a currently unknown proportion of genetic variants. Third, as discussed below, almost all of these studies evaluated common genetic variation. RESULTS We evaluated these 25 historical candidate genes for schizo- Table 1 summarizes 25 historically important candidate genes for phrenia in four ways. First, we conducted fixed-effects meta- schizophrenia. For 24 of 25 genes, the initial study conducted analyses for all genetic markers in these 25 genes using summary genotyping to evaluate the impact of common genetic variation data on subjects of European
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