Gene 535 (2014) 97–100

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Review

Genetic insight of schizophrenia: past and future perspectives

Shweta singh a, Ashok Kumar a, Sarita Agarwal a,⁎, Shubha R. Phadke, Yamini Jaiswal b

a Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, Indiab Life care hospital Cant. Gorakhpur (UP)-273001, India

Abbreviations: SCZ, Schizophrenia; ID, Intellectual disaSingle nucleotide polymorphism; CNVs, Copy number vDizygotic; FISH, Fluorescence in-situ hybridization; GWstudy.⁎ Corresponding author. Tel.: +91 522 2494349 (office

522 2668017.E-mail addresses: shwetasinghpgi@gmail.com (S. sing

chemistry.ashok83@gmail.com (A. Kumar), saritasgpgi@gshubharaophadke@gmail.com (S.R. Phadke), yamini_jaisw

0378-1119/$ – see front matter © 2013 Published by Elsehttp://dx.doi.org/10.1016/j.gene.2013.09.110

a b s t r a c t

a r t i c l e i n f o

Article history:Accepted 26 September 2013Available online 17 October 2013

Keywords:SchizophreniaMental retardationBipolar disorderGWASMeta analysis

Schizophrenia (SCZ) has a heritability of about 80%, and the search for the genetic basis of this disease has beenfrustrating. Because schizophrenia has no distinguishing pathology or diagnostic criteria, it is difficult to relategene changes to discrete physiological or biochemical changes associated with the disease. Schizophrenia fitsthe profile of a complex disorder in which multiple genes interact along with environmental influences toproduce a range of phenotypes. There is accumulating evidence that both common genetic variants with smalleffects and rare genetic lesionswith large effects determine risk of SCZ. As recently shown, thousands of commonsingle nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of theunderlying genetic risk of SCZ. The ability of positional genetics to implicate novel genes and pathways willopen up new vistas for neurobiological research, and all the signs are that genetic research is poised to delivercrucial insights into the nature of schizophrenia. In this review, we outline a general theoretical background ofgenetic mechanisms involved in SCZ.

© 2013 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972. Clinical genetic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983. Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

3.1. Linkage and positional cloning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983.2. Signal transduction hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983.3. Molecular–genetic hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993.4. Neural network hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

4. Molecular genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

1. Introduction

Neurodevelopmental disorders are characterized by impairment ofgrowth and development of the brain often associated with cognitive,

bility; BD, Bipolar disorder; SNP,ariants; MZ, Monozygotic; DZ,AS, Genome wide Association

), +91 9415336601; fax: +91

h),mail.com (S. Agarwal),al@yahoo.com (Y. Jaiswal).

vier B.V.

neurological, or psychiatric dysfunction. It is an umbrella termthat can traverse, to varying degrees, diverse disease classificationsincluding intellectual disability (ID), developmental delay (DD), autism,schizophrenia (SCZ), bipolar disease (BD), etc. Despite seeminglydistinct primary diagnoses, considerable clinical heterogeneity, aswell as overlap, has been appreciated for many years. Individuals withschizophrenia, for example, can present with symptoms such asdelusions, hallucinations, loosening of associations, disorganized speechand behaviour, illogical thinking, social isolation and cognitive deficit.Similarly, it is well known that individuals with schizophrenia alsodemonstrate co-morbidity with cognitive impairments of varyingseverities (Woodberry et al., 2008) as well as, in some cases, structuraldefects of the brain (Weinberger and Lipska, 1995). Schizophrenic

Table 1Schizophrenia genes at a glutamatergic synapse and their function.

DISC1 Disrupted-in-schizophrenia 1Dysbindin(DTNBP1)

Synaptic structure and function in the brain

NEUREGULIN 1(NRG1)

Regulator of glial cells and myelination

RGS4 Regulator of G protein signalling-4COMT Encodes COMT glutamatergic co-activator, degrades dopaminePDE4B Regulates signal transductionDAAO Encodes for D amino acid oxidase involved in D serine

metabolismGRM1 Modulator of neuronal signalling and synaptic plasticityPSD95 Anchoring of synaptic proteinsErbB-4 Encodes tyrosine-protein kinase ErbB-4 receptor for

Neuregulin1NRGN Encodes for neurogranin involved in protein kinase C signalling

pathwayGRM3 Encodes metabotropic glutamate receptor

98 S. singh et al. / Gene 535 (2014) 97–100

patients are more prone to seizure (Cascella et al., 2009; Hyde andWeinberger, 1997). There are convincing epidemiological links betweenthese diseases that support amodel that at least part of the etiologymaybe neurodevelopmental in origin (Weinberger, 1987). The genetics ofthese diverse conditions have also begun to converge. Large copynumber variants (CNVs), in particular, have been implicated in thesediseases to different degrees. This has included reports of overallincreases in CNV burden, higher rates of de novo or sporadic mutation,and the discovery of specific recurrent CNVs observed across diversephenotypes. With few exceptions, CNVs have been large affectingnumerous genes and are extremely rare for any specific locus (b1%) butcollectively common on the whole. An emerging model has been certainthat CNVs disrupt the homeostasis of normal neuronal developmentresulting in range of disorders as a part of neurodevelopmentalcontinuum (Stefansson et al., 2008; International SchizophreniaConsortium, 2008; Helbig et al., 2009). Schizophrenia researchers arefacedwith the additional obstacle of a disorder entirely defined by historyand clinical examination, there being no investigations to confirmdiagnosis, to separate the syndrome from unrelated disorders or to aidin sub-classification. These difficulties together with early failures toobtain clear replication of linkages led to increasing scepticism thatgenetic approaches would ever be successful. The purpose of this workis to briefly describe the influences of genetic and environmental factorsin schizophrenia and putmore emphasis on aspects of the clinical geneticevaluation, molecular diagnosis and counselling.

2. Clinical genetic evaluation

Once the neuropsychological diagnosis of a schizophrenia disorder isestablished, it is crucial to proceed with a medical examination in orderto detect concomitant issues that require treatment. Among thosediverse arrays of adverse gestational events that have been associatedwith schizophrenia such as fetal hypoxia, obstetric complications,maternal infection/immune function, season of birth and maternalstress hampers the search for a common aetiology (van et al., 2010),although polymorphisms within enzymes involved in dopamine (DA)turnover such as mono-amine oxidase A and catechol-o-methyltransferase or DA 2 and 3 receptors rank highly among such candidatesgenes (Need et al., 2009). In addition, a clinical genetics evaluationshould be considered in schizophrenia in order to identify syndromicform of schizophrenia, identify familial cases, and drive diagnostictesting. Schizophrenia, a major mental disease, affects approximately1% of individuals worldwide. Several reports support an associationbetween SCZ and environmental factors such as birth in winter orearly spring, urban birth, paternal age, famine, and nutritional andperinatal complications (Abdolmaleky and Thiagalingam, 2011). Twinstudies of schizophrenia (Cardno and Gottesman, 2000) estimate therelative importance of genes and environment in liability and showconsistently higher concordance in monozygotic (MZ, B50%) thandizygotic (DZ, B17%) twins. Thus, schizophrenia is largely geneticallymediated but not genetically determined. Risk of SCZ was present inthe biological relatives of individuals with schizophrenia (Prescott andGottesman, 1993). In 361 families in Finland, 4.9% of adopted awaychildren of schizophrenic mothers have SCZ and 9.1% have a SCZspectrum disorder, whereas 1.1% of adopted away offspring of controlmothers have SCZ (Tienari et al., 1991). The clinical genetic evaluationcan recognize phenotypes related to known genetic conditions suchas the 22q11 microdeletion, which is associated with schizophreniaand velocardiofacial syndrome 42, as well as anxiety, depression,attention-deficit hyperactivity disorder, obsessive-compulsive disorderand autism spectrum disorders (Gothelf et al., 2004). The mostcommonly associated deletions are identifiablewith standardmolecularcytogenetic studies, now available in clinical laboratories, using afluorescence in-situ hybridization (FISH) technique and 22q11.2 probesD22S75 or TUPLE1 (Anne et al., 2002). It should be kept in mind that inmost of monozygotic form of schizophrenia, such as those caused by

mutations in neuroglins, SHANK3, FOXP2, SOX10 and many others(Iwamoto et al., 2005), there is no recognizable phenotype that drivesthe testing towards one gene or another.

3. Genetic factors

Schizophrenia is a severe mental illness, with heritability estimatedat over 80% and onset in adolescence or early adulthood with anincreased recurrence risk (more than 50%) in monozygotic twins andin first degree relatives (Cardno et al., 2000). This observation pointsto a major genetic contribution. However, despite significant research,including high throughput technique applications, efforts have failedto identify genes of large-effect, whose identifications could impactstrongly the diagnosis, prognosis and counselling to schizophreniafamilies. The outstandingquestion is:Where is the heritable componentof schizophrenia?

3.1. Linkage and positional cloning

Three of the best supported regions are 6p24–22, 1q21–22 and13q32–34 where single studies have achieved genome wide significanceat P b 0.05 (Brustowicz et al., 2000). In large cohorts of patientswith schizophrenia, some genomic ‘hotspots’ harbor multiple structuralvariants strongly associated with the disease. For example, deletionsat four different loci, 1q21.1 (Consortium, 2008), 15q11.2, 15q13.3(Stefansson et al., 2008) and 22q11.2 (Karayiorgou et al., 1995), aresignificantly over-represented in schizophrenia patients compared withcontrols. In a recent meta-analysis of 20 schizophrenia genome scans,the number of loci meeting aggregate criteria for significance was muchgreater than the number of loci expected by chance (Pb0.001), revealinggreater consistency than has been previously recognised (Lewis et al.,2002). Another meta-analysis (Badner and Gershon, 2002) foundsignificant results only on chromosomes 8p, 13q and 22q. The evidencefor multiple linkage regions in schizophrenia begs the question of whichwarrant extensive efforts aimed at identifying the susceptibility loci.Though these studies present a low replication, more evidence supportsthat the etiology of SCZ involves, rather than single genes/loci with largeeffect, many genes, each of which contributes a small risk, interactingwith each other orwith environmental risk factors to cause schizophrenia(Purcell et al., 2009). It is increasingly possible to investigate biologicalnetworks/pathways of SCZ because of the rapid accumulation of geneticand biological information in the past decade. There are three proposedmodel of the pathophysiology of SCZ.

3.2. Signal transduction hypothesis

The signal transduction hypothesis posits that basic alterationsin receptor-medicated signal transduction induce schizophrenia-like

Table 2Summary of the supporting evidence for the schizophrenia susceptible region.

Study providing support Population studied Study Statistical evidence Region/gene

Allen et al. (2008) U.S. (Afro-American) Meta-analysis OR1.23 MultigenicLewis et al. (2005) – Meta-analysis OR1.48 1p36 (MTHFR)Muntjewerff et al. (2005) – Case–control OR3.3 1p36 (MTHFR)Brzustowicz et al. (2000) Canadian Genome wide scan lod score 6.5 1q21-q22 (NOS1AP)Levinson et al. (2002) Multicenter Genotyping MLS¼3.1 1qMirnicsa et al. (2001) Multicenter Genome wide scan 1q(RGS4)Cao et al. (1997) European-American/African-American Genome wide scan MLS¼3.06 6q21-25Kaufmann et al. (1987) African-American – NPL¼2.27 8pter–q12Gill et al. (1993) Multicentre collaboration – w2¼9.31,P¼0.001Delisi et al. (1991) Europe/Chile – Zmax¼3.6 22q12, 10p12Gurling et al. (2001) Iceland/UK – MLS¼3.2 8p22.1–22DeLisi et al. (1981) Costa Rica – MLS¼1.78 5q21–31Hovatta et al. (1999) Finland (isolate) – Zmax¼3.8 1q32.2–q41

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psychopathology. Therefore, normalizing the altered signalling withmedications targeting receptor and post-receptor molecules should beefficacious in treating schizophrenia (Javitt, 2004).

3.3. Molecular–genetic hypothesis

The molecular–genetic hypothesis posits that strong effects ofsusceptibility genes underlie the pathophysiology of schizophrenia(Harrison et al., 2005), and suggests that targeting drugs at these genesor their associated anatomic and functional pathways might yield noveland more effective treatments for schizophrenia susceptibility genes inschizophrenia, including dysbindin, neuregulin 1, COMT, and DISC1.Interestingly, many of these genes appear to be related to the control ofsynaptic plasticity and glutamate transmission particularly NMDAreceptor function (Rapoport et al., 2005).

3.4. Neural network hypothesis

The neural network hypothesis proposes that schizophrenia resultsfrom the strong effects of altered neuronal integration. This hypothesispredicts that drugs that fundamentally reset the tone of networks ofneuronal interactions will prove efficacious in treating schizophrenia(Spedding et al., 2005). Neurodevelopment disorder associated withabnormal connectivity results from defects in synaptic pruning andmigration of neurons. If alterations in synaptic pruning are the primaryprocess underlying the pathophysiology of SCZ, possibly due toinherited genetic alterations in genes such as DISC1 or dysbindin, theneffective treatment strategies should target the underlying deficits.The genes related to the proposed model of pathophysiology of SCZare discussed in Table 1.

4. Molecular genetics

SCZ gene database represents the first comprehensive onlineresource for systematically synthesized and graded evidence of geneticassociation studies in schizophrenia. Allen et al., (2008) showed that intheir study 94, or 80%, of the SNPs in 45 genes showed no significantassociation with schizophrenia. A total of 38 genes were found to beassociated with at least one endophenotypic measure or schizophreniawith an empirical P valueof b0.01. The GWAS studies for schizophreniaand other psychiatric disorders have not been as successful as in otherdiseases or traits such as cancer, body mass, and height (Sullivan2010). Other conducted case–control analysis of 568 patients withschizophrenia and 689 controls failed to confirm support for associationof specific RGS4 SNP alleles or for association of a particular 4, 3, or 2 SNPhaplotypes. This study investigated the same SNPs and haplotypesfound to be associated with schizophrenia in other studies (Sobellet al., 2005). Hodgkinson et al. (2004) also found overrepresentationof a missense allele of the DISC1 gene, leu607 to pro, in schizoaffectivedisorder. These data supported the idea that these apparently distinct

disorders have at least a partially convergent etiology and that variationat the DISC1 locus predisposes individuals to a variety of psychiatricdisorders. Knight et al. (2009) resequenced ABCA13 exons in 100cases with schizophrenia and 100 controls. Multiple rare codingvariantswere identified including1 nonsense and 9missensemutationsand compound heterozygosity/homozygosity in 6 cases as discussed inTable 2.

Authors’ contributions

Shweta Singh and Ashok Kumar are responsible for the conceptionand designing of the manuscript. Contributing authors Sarita Agarwaland Shubha Phadke made substantial contributions to the design ofthe manuscript and the acquisition.

Conflict of interests

There is no conflict of interests.

Acknowledgments

We thank Sanjay Gandhi Post Graduate Institute of Medical Sciences(SGPGIMS), Lucknow, and Department of Science and Technology(DST) and Department of Biotechnology (DBT), New Delhi, India, forproviding infrastructure facility to carry out research work and Prof.Sarita Agarwal for proper guidance and Dr. Shubha for providing clinicalsupport.

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