GENETICS (V BONIFATI, SECTION EDITOR)

Schizophrenia Genetics: Putting All the Pieces Together

Simon L. Girard & Patrick A. Dion & Guy A. Rouleau

Published online: 30 March 2012# Springer Science+Business Media, LLC 2012

Abstract Schizophrenia is a major mental disorder charac-terized by a deep disruption of the thinking process and ofemotional response. For many decades, genetics studieshave yielded little success in identifying genetic factorsresponsible for the disease. However, with the recent break-throughs in genome analysis technologies, the field of thegenetics of schizophrenia has progressed a lot in the lastyears. Both common and rare variants have been success-fully associated with the disease and a particular emphasishas been made on rare copy number variations. Recently, anew paradigm linking de novo mutations to the geneticmechanism of schizophrenia has been unravelled. The aimof this review is to discuss the most important geneticstudies made in the field to give a general perspective ofwhere to go in the future.

Keywords Schizophrenia . Genetics . Genomics . GWAS .

Genome-wide association study . Sequencing .

Next-generation sequencing . De novo . CNV. Copy number

variation . Linkage studies . Psychiatric disorder . Mentaldisorder

Introduction

Schizophrenia (SCZ) is a well-known psychiatric disease forwhich no presentation is needed as it is very often depictedin the popular media, although not always in the mostaccurate manner. Despite this general awareness, and therelatively high prevalence of this disorder (1.1 % of the USadult population according to the National Institute of Men-tal Health), the disease still has a strong negative stigmati-zation and is too often a taboo subject. Moreover, accordingto the World Health Organization, nearly half the patientswith a diagnosis of SCZ are not receiving appropriate healthcare for the relief of their symptoms. This may be in part dueto the fact that SCZ symptoms are often confused with thoseobserved in other mental disorders (eg, psychotic depressionor bipolar disorder [BP]) [1]. The aim of this review is toprovide a synopsis of the most important genetic studies thatwere made in the field of SCZ in the past decades. With suchan outlook in mind, we do not wish to make an exhaustivereview of all literature investigating the genetics of SCZ, asthis task would yield data for a complete book. But, webelieve that even a short overview of the matter will helpmake clearer the novel perspectives brought on by the mostrecent findings. It has been shown multiple times that SCZis a very complex disorder and to undertake a comprehen-sive study on the genetics of this disease, one must be awareof previous work to have a full perspective of the study.

Is Schizophrenia a Genetic Disorder?

The contribution of genetics to the pathogenesis of SCZ hasbeen widely reported. When it comes to establishing the

S. L. Girard : P. A. Dion :G. A. Rouleau (*)Centre of Excellence in Neuromics of Université de Montréal,Centre Hospitalier de l’Université de Montréal Research Center,Montréal, Québec, Canadae-mail: guy.rouleau@umontreal.ca

P. A. DionDepartment of Pathology and Cellular Biology,Université de Montréal,Montréal, Québec, Canada

G. A. RouleauCentre of Excellence in Neuromics of Université de Montréal,Centre Hospitalier Universitaire Sainte-Justine Research Center,Montréal, Québec, Canada

G. A. RouleauFaculty of Medicine, Department of Medicine,Université de Montréal,Montréal, Québec, Canada

Curr Neurol Neurosci Rep (2012) 12:261–266DOI 10.1007/s11910-012-0266-7

molecular basis of a disease, one has to try to evaluate thecontribution of underlying genetic and environmental path-ogenic contributions. Twin studies, which over past decadeswere broadly used for the investigations of various disor-ders, are ideal to establish the total heritability that can beattributed to genetic factors. Fortunately, many twin studieshave been conducted for SCZ based on selected proband [2,3], systematic selections [4, 5], or specific populations [6,7]. They all document a substantially higher disease concor-dance in monozygotic twins versus dizygotic twins. Further-more, a meta-analysis of 12 twin studies established theheritability of SCZ to be around 81 % [8], which stronglyargues in favor of an important genetic architecture under-lying this disease. The same meta-analysis also conclusivelydemonstrated that SCZ is a complex trait that not onlyinvolves multiple genetic factors, but also environmentalfactors. To keep this review of a reasonable size, we onlyfocus on genetic factors.

The Cornerstone of Schizophrenia Genetics: LinkageStudies

A linkage study is a statistical test used to test if a chromo-somal region is linked to a specific trait using one or manyfamilies’ recombination events. Its extensive use hasallowed the discovery of a large number of genes and locifor various inherited disorders that were deemed to bemonogenic. Many linkage studies have been performed infamilies where many cases of SCZ were observed; thisincludes at least 25 independent genome-wide linkage scans[9]. However, only a few regions were subsequently repli-cated. The first linked region was reported in 1994 onchromosome 22q13.1 in a Maryland family [10]. However,no gene in the identified locus was conclusively linked tothe disease. A subsequent report based on an Icelandicpopulation made a more conclusive discovery: the identifi-cation of two risk haplotypes within the Neuregulin1(NRG1) gene (chr8p22-p21) [11]. Over the years, this par-ticular linkage has been replicated in many populations andmolecular findings support the implication of this particulargene [12]. Interestingly, recent evidence has linked NRG1with Disrupted in Schizophrenia 1 (DISC1) [13], anotherprominent and much investigated SCZ susceptibility gene.One last important association that came from a linkagestudy was the identification of a linked region that harborsthe dystrobrevin-binding protein 1 (DTNBP1) gene. Con-clusive molecular data now exist to support the notion thatDTNBP1 contributes to the etiology of SCZ [14]. Manyother SCZ linkage studies were reported but we believethe ones highlighted here are the most robust. Altogether,linkage studies in SCZ were very successful; they not onlyidentified genes linked to the disease but they also

demonstrated that SCZ can be, rarely, a trait transmitted ina monogenic way in a family.

A Special Case: DISC1

DISC1 was found to be associated with SCZ in a Scottishfamily carrying a translocation on chromosome 1 [15].Several years later, this translocation was found to directlydisrupt a gene, which henceforth became referred to asDISC1 [16]. The protein encoded by DISC1 appears to havemultiple cellular functions, particularly in the regulation ofthe nervous system development and brain maturation;DISC1 has been shown to be involved in neuronal prolifer-ation, differentiation, and migration via various signalingpathways [17]. DISC1 is not only an important risk factorfor SCZ, it is also believed to contribute to the developmentof other major psychiatric disorders such as BP and majordepression [17]. At this point, it remains one of the strongestassociations [17] observed between a gene and SCZ.

Lost in the Mists of Genome-Wide Association Studies

Genome-wide association studies (GWAS) have been the mostwidely reported genetic approach of the past decade. Theprinciples underlying this approach are fairly simple, althoughthe application of the method is complicated: it is a case–control study that compares the frequency of alleles spreadthroughout the genome between a cohort of cases and a cohortof controls. While this approach was tremendously successfulin identifying risk factors for many multifactorial disorders, itsuse for diseases like SCZ was a disappointment.

The first wave of GWAS quickly revealed the complexmultifactorial aspect of SCZ because nearly no positiveassociations could be observed [18–21]; most of the associ-ation signals identified were never replicated in the follow-ing waves of SCZ GWAS. The only positive associationobserved during the first wave of SCZ GWAS that is worthmentioning is the associations around ZNF804A [22]. Thisassociation has since been confirmed in many replicationstudies [23, 24]. Other than its recently demonstrated role inneural cell adhesion [25], little to nothing is known aboutthe function of ZNF804A, and further molecular studies arenow required to assess its role in the disease. In 2009, twolarge-scale GWAS of SCZ were published back to back andboth found an association with the major histocompatibilitycomplex (MHC) region [26•, 27•]. To date, this associationwith the MHC is the strongest association ever found by anytype of genetic study for SCZ. This robust association was asurprise as the MHC region harbors a large number ofimmune-related genes and it had been previously associatedwith many autoimmune and infectious disorders [28].

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Does that mean that SCZ results in part from an alteredimmune response? Possibly, as a number of cases have beenreported where an autoimmune encephalitis leads to prom-inent psychiatric syndromes. It may be that a fraction ofSCZ cases results from such an immune mechanism, withcertain MHC alleles playing a role. Alternatively, it is pos-sible that the MHC Class I may have a role in brain function,perhaps in the synapse [28]. Other than the MHC, those twolarge-scale GWAS identified new potential association forthe genes TCF4, NRGN [26•], and MYO18B [27•] as well asa replication of the ZNF804A association.

A recent wave of three independent SCZ GWAS, twousing the Han Chinese population [29, 30] and another oneusing an impressive discovery set of over 20,000 individualsof European ancestry [31••], was very recently reported. Thefirst striking fact is that the two GWAS using the HanChinese population were not concordant. The first one iden-tified two new loci on 1q24.2 and 8p12 [29]. The secondone replicated the association with the MHC loci and ob-served a positive signal on 11p11.2 [30]. It is somehowsurprising that two studies made on the same populationdon’t identify the same loci. In this case another study,independent from the first two, would be required to assesswhich of the associations are robust. The third GWAS con-ducted with the European ancestry samples replicated twopreviously identified loci (MHC and TCF4) and identifiedfive novel loci (1p21.3, 2q32.3, 8q21.3, 8q21.3, 10q24.32)[31••]. The most interesting of these novel loci is the one onchromosome 1 that contains a predicted target of the micro-RNA 137 (MIR137). It has been previously shown thatMIR137 plays an important role in neuron maturation byacting at the level of dendritic morphogenesis, phenotypicmaturation, and spine development. It is noteworthy thatseveral target genes of MIR137 were shown to play impor-tant roles in several human cancers [32, 33], as well as incell cycle signaling [34], and mouse embryonic stem celldevelopment [35]. The implication of MIR137 in SCZ is aplausible hypothesis but more work is needed to understandhow it may impact on the pathogenesis.

Nonetheless, despite these positive associations, the suc-cess of SCZ GWAS studies is mitigated as most of thepreviously identified loci could not be replicated in the mostrecent studies. Does that mean that common variants do notplay a significant role in the etiology of SCZ? Of course not.The identification of the associations within the MHC is amajor discovery that has opened a whole new field of studywithin the research on SCZ. However, for the other associ-ations, with the exception maybe of TCF4 and ZNF804A, itis unclear if they are true signals or just study artifact that arein no way linked to the disease. We believe that the marginalsuccess of GWAS in SCZ teaches us a lot about the hetero-geneity of the disease, not only from a genetic point of view,but from a clinical perspective. This is consistent with the

ongoing difficulties in establishing clear subphenotypes forthe clinical classification. The heterogeneity of SCZ can alsobe demonstrated by the fact that many genes are commonacross psychiatric disorders that have distinct clinical man-ifestations. Thus, a combinatory genetic and environmentaleffect could result in different symptoms and make it moredifficult to reduce the heterogeneity of a cohort and maxi-mize the detection power.

The Challenges of CNV Studies

Even today, copy number variations (CNVs) are probablythe most difficult genetic variation to reliably identify. Thebroad range, sizes (from a few hundreds of base pair to afew megabases), and nature (deletion, duplication, inver-sion, etc…) make it very difficult to have a realistic portraitof the implications of CNVs in a disease. Nonetheless, manysuch studies have been successful with the identification ofCNVs that increase the odds of being affected with SCZ. Itwas first demonstrated that SCZ patients seem to carry moreCNVs than expected: a recent comparative genomic hybrid-ization study revealed that the general prevalence of rarestructural variant is higher in SCZ patients than in popula-tion controls [36•]. Another CNV study, this time usingsingle nucleotide polymorphism (SNP) genotyping arrays,confirmed this observation but it added another element,that SCZ patients carry more de novo CNVs than controls[37]. Finally, a third study further established that the CNVburden, defined as the number of CNVs per individual incombination with the number of genes per CNVs, is higherin SCZ patients than in controls, thus hinting the fact thatrare CNVs in SCZ would not only be more frequent, butalso more damaging [38]. This last study also identifiedCNV loci associated with increased risk for the disease on1q21.1, 15q13.3, and 22q11.2. Surprisingly, two of theseloci (1q21.1 and 15q13.3) have been replicated in a secondgenome-wide CNV study [39•]; the study also identified anew locus on 15q11.2. The fact that those two studies arevery concordant with each other is a striking difference fromthe GWAS, thus suggesting that rare variants could have alarger effect of the disease. Afterward, three additional CNVstudies identified several new associated loci on 3q29 [40],16p11.2 [41], and 16p13.1 [42].

In addition to the identification of many CNV loci asso-ciated with SCZ, those studies were all concordant on onepoint: the association of CNV with the disease is restrictedto rare or de novo variations. No study has been able toidentify a common CNV that is associated with an increasedrisk of developing SCZ. Although CNV studies still remainlimited in their range of detection as well as in their popu-lation size (when compared to previous GWAS studies), wethink it is unlikely that common CNVs predisposing to SCZ

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will be found. A study looking at eight common disordersdemonstrated that common CNVs are well tagged by SNPs,so their existence has already been explored indirectlythrough the large GWAS studies [43••]. Thus, commonCNVs are unlikely to contribute greatly to the genetic basisof those diseases, which included BP. Even if BP is verydifferent from SCZ, many studies have shown a great over-lap in their genetic mechanism as BP has also been linked torare de novo CNVs [44]. It would make sense to supposethat the conclusions found for BP may also apply to SCZand, thus, it appears unlikely that common CNVs are con-tributing significantly to the etiology of the disease.

A New Paradigm: De Novo Mutations

Recently, a new hypothesis has started to emerge in the field ofSCZ: the implication of de novo mutations (ie, mutationsarising sporadically either in the gamete cells of the parentsor at the early stage of embryo development). This hypothesishas really started to blossom in the last 2 years, with identifi-cation of genes by hypothesis-driven gene sequencing. Acritical stage was reached by the identification in patientsaffected with SCZ of two de novo mutations in SHANK3;one of the two mutations leading to a premature stop codon[45•]. Shortly after, other genes were found to harbor de novomutations linked to SCZ, of which included KIF17 [46] andNRXN1 [47]. Pulling together data from a large synaptic generesequencing project, it was shown that there was an excess ofpotentially deleterious de novo mutations in SCZ [48•]. Veryrecently, the new sequencing technologies have been used totest this hypothesis. A first study using exome capture hasshown that not only did SCZ patients have a higher thanexpected exonic de novo mutation rate, but they also exhibita nonsense/missense ratio very similar to pathogenic Mende-lianmutations [49••]. A second study supported these findingsby identifying 40 de novo mutations in 53 SCZ patients with alarger than expected number of nonsynonymous changes[50••]. The studies reporting de novo mutations in SCZ areconcordant and clearly support that such mutations wouldexplain a fraction of sporadic SCZ cases. These results arestrengthened by the fact that similar studies have successfullydemonstrated the implication of de novo mutation in othermajor psychiatric disorders such as autism spectrum disorder[51] and mental retardation [52]. Thus, it would seem that denovo mutations are an important mechanism to take intoaccount for the planning of future SCZ studies.

Conclusions

Not many diseases can claim to encompass a genetic portraitas complex as the one now emerging for SCZ. Over the

years, researchers have focused on a broad range of genetichypotheses and in the end they are all, to some extent,involved in the big picture of the disease. To this day, nosingle gene can explain a significant fraction of the SCZcases. While it is likely that the great heterogeneity seen inSCZ explains why it is so hard to identify common variants,the identification and exploitations of more informativeendophenotypes may at one point help to resolve that issue.In the mean time, it is clear that we are facing a disease forwhich many of the genes responsible still have to be iden-tified. It would not be surprising if hundreds of genes wereto be involved in the disease. We predict that as more andmore SCZ-predisposing genes are identified, many willcoalesce into pathways that will greatly increase our under-standing of the disease as well as open up new therapeuticapproaches.

Disclosure Conflicts of interest: S.L. Girard: none; P.A. Dion: none;G.A. Rouleau: none.

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