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The Emerging Spectrum of Allelic Variation in Schizophrenia

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The Emerging Spectrum of Allelic Variation in Schizophrenia Molecular Psychiatry (2013) 18, 38 -- 52 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp EXPERT REVIEW The emerging spectrum of allelic variation in schizophrenia: current evidence and strategies for the identification and functional characterization of common and rare variants BJ Mowry1,2 and J Gratten1 After decades of halting progress, recent large genome-wide association studies (GWAS) are finally shining light on the genetic architecture of schizophrenia. The picture emerging is one of sobering complexity, involving large numbers of risk alleles across the entire allelic spectrum. The aims of this article are to summarize the key genetic findings to date and to compare and contrast methods for identifying additional risk alleles, including GWAS, targeted genotyping and sequencing. A further aim is to consider the challenges and opportunities involved in determining the functional basis of genetic associations, for instance using functional genomics, cellular models, animal models and imaging genetics. We conclude that diverse approaches will be required to identify and functionally characterize the full spectrum of risk variants for schizophrenia. These efforts should adhere to the stringent standards of statistical association developed for GWAS and are likely to entail very large sample sizes. Nonetheless, now more than any previous time, there are reasons for optimism and the ultimate goal of personalized interventions and therapeutics, although still distant, no longer seems unattainable. Molecular Psychiatry (2013) 18, 38--52; doi:10.1038/mp.2012.34; published online 1 May 2012 Keywords: CNV; functional genomics; GWAS; schizophrenia; sequencing; SNP THE NATURE OF THE PROBLEM complications (obesity, nicotine dependence, metabolic syndrome 13 Schizophrenia is a chronic psychiatric disorder characterized by and premature mortality), low employment and substantial 14 delusional beliefs, auditory hallucinations, disorganized thought homelessness. The disorder ranks ninth in the global burden of and behaviour, negative symptoms, and cognitive deficits illness, and ranks fifth (males) and sixth (females) in the leading 15 producing profound impairment of emotional and social behav- global causes of years lost because of disability. iour. Onset of psychosis is typically in late adolescence or early Despite the magnitude of its disease burden, the aetiology of adulthood, although subtle, nonspecific signs such as delayed schizophrenia remains poorly understood. The prevailing hypoth- 16--18 milestones1 and reduced intelligence quotient2 predate psychosis esis is that schizophrenia is a neurodevelopmental disorder, onset. These data are consistent with a reformulation of illness but the underlying molecular and cellular mechanisms remain a comprising pre-symptomatic risk, prodrome, acute psychosis and mystery. Diverse aetiological clues, including family history, early chronic illness.3 The schizophrenia phenotype is defined accord- life adversity, urban upbringing, migrant status, cannabis use and 19 ing to reliable international criteria (DSM-IV; ICD-10), but is a variety of pre/perinatal factors, have emerged from a large 20 nonetheless heterogeneous and is generally thought to comprise body of epidemiological studies. By far the most compelling of an amalgam of related disorders, a plurality that was proclaimed in these is family history, recognized for almost a century since the title of Bleuler’s classic 1911 text, ‘Dementia praecox or the Kraepelin observed ‘dementia praecox not at all infrequently is 21 group of schizophrenias’.4 Over the subsequent 100 years, many familial, often appearing in brothers and sisters’. Decades of attempts have been made to carve schizophrenia ‘at its joints’ in family, twin and adoption studies have established high 22,23 order to develop homogeneous sub-types for more intensive heritability (81%, confidence interval: 73--90%), which has aetiological study. The deficit syndrome,5 and antipsychotic compelled the search for genetic variation contributing to disease. treatment resistance6 serve as examples. In parallel with this drive to refine, is the more recent trend, based on accumulating evidence, to question the ‘Kraepelinian divide’ between schizo- THE PRE-GWAS ERA phrenia and bipolar disorder.7 Before the development of genome-wide association study Lifetime prevalence for established illness is B0.72%8 and the (GWAS) methodology, genetic studies of schizophrenia relied on suicide rate is B7%, the majority occurring in the first 3 years after karyotyping, linkage studies and candidate gene association onset.9 Only a minority (o14%) experience sustained recovery studies. Two of the best-known chromosomal rearrangements within the first 5 years of illness10 and another 16% later in the are large deletions on chromosome 22q11.2 and a balanced illness.11 Current treatments have limited efficacy (80% relapse chromosomal translocation t(1:11) (q43,q21) that led to the rates)10 and financial costs are high (for example, E94 billion for discovery of the DISC1 (disrupted-in-schizophrenia 1) gene. The psychotic disorders in Europe, 2010),12 with attendant medical chromosome 22q11.2 deletion syndrome (22q11.2DS) occurs in 1 1Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia and 2Queensland Centre for Mental Health Research, Wacol, Brisbane, Queensland, Australia. Correspondence: Professor BJ Mowry, Queensland Brain Institute, Building # 79, Upland Road, The University of Queensland, Brisbane, QLD 4072, Australia. E-mail: [email protected] Received 30 January 2012; revised 23 February 2012; accepted 19 March 2012; published online 1 May 2012 The emerging spectrum of allelic variation in schizophrenia BJ Mowry and J Gratten 39 in 2000--4000 live births.24,25 Most carriers of the 22q11.2DS have complex disease.45,46 GWAS methodology has been facilitated either a 3 or 1.5 Mb deletion, affecting between 30 and 60 by technological advances that enable the simultaneous and primarily brain-expressed genes. Unsurprisingly, this syndrome cost-effective analysis of large numbers of genetic markers (that is, displays extensive phenotypic heterogeneity including a range of up to 5 million) that tag a high proportion of all common single physical manifestations, cognitive impairments and behavioural nucleotide polymorphisms (SNPs) in the human genome. disturbances.25 One example is the velocardiofacial syndrome Although designed primarily to identify common small effect (palatal dysfunction, ventricular septal defects, dysmorphic facies alleles hypothesized under the common disease common variant and learning disabilities),26 the syndrome most frequently hypothesis, data from GWAS arrays can also be used to identify reported as having both the deletion (85--100%) and psychosis, rare submicroscopic chromosomal deletions and duplications in particular schizophrenia (up to 30%).27--29 Moreover, 22q11.2DS known as copy number variants, or CNVs. Recent years have seen occurs more frequently in schizophrenia than in the general a spate of reports identifying common, polygenic and rare variants population,30 and there does not appear to be any significant in schizophrenia, hinting at a large number of risk alleles across clinical differences in schizophrenia with or without 22q11.2.31 the entire allelic spectrum. Support for this locus has strengthened with the application of GWAS methodology and it is now widely accepted as the Common variation most robust association in schizophrenia (see below). The The first GWAS for schizophrenia were reported in 2006--2007.47,48 chromosomal translocation involving DISC1 and a non-coding These and other early studies49--52 failed to identify loci surpassing RNA named DISC2 (ref. 32) was first identified in a four- modern standards for genome-wide significance (P 5 Â 10À8), generational Scottish pedigree33 in which the proband had severe o presumably because sample sizes were inadequate for the effect conduct disorder.34 The translocation is strongly associated with sizes that we now know are typical of common variants in psychiatric disorders in this pedigree, including recurrent major complex neuropsychiatric disorders. The community has since depression, bipolar disorder and schizophrenia, with strongest coalesced into large international consortia with impressive statistical support for a broad, cross-disorder clinical phenotype.35 results: the number of studies (including meta-analyses) reporting A large body of functional work motivated by the initial discovery SNPs with genome-wide support has risen to 9 (refs 53--61) supports an important role for DISC1 in neurodevelopment,36 but (Table 1), and the total number of genome-wide significant loci statistical support from linkage and association studies in has grown to 12, some of which include evidence for multiple schizophrenia is lacking in populations other than the focal independent associations (for example, 10q24.3, 11q24.2, family.37,38 18q21.2). Additionally, four other loci have been identified in Linkage analysis assesses the co-segregation of genetic loci joint analyses of schizophrenia and bipolar disorder,57,61 consis- with disease in families. This strategy has been very successful for tent with clinical and epidemiological evidence for shared genetic Mendelian traits, but less so for complex diseases. In schizo- aetiology between these disorders (see below). As for other phrenia, over 30 genome-wide linkage analyses have been complex diseases, the
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