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Copy Number Variations in Schizophrenia: Rare But Powerful?

27 March 2008. Rare structural variations in the genome—resulting in duplicated, deleted, or simply disrupted gene copies—may exert profound effects on the pathogenesis of individual cases of schizophrenia, according to researchers who published genome-wide analyses of two separate groups of individuals with the disorder today in Sciencexpress. In one sample, subjects with schizophrenia or schizoaffective disorder were three times more likely than control subjects to have deletions or duplications (also known as copy number variations, or CNVs) of genomic sequences ranging from thousands to millions of nucleotides. In the second sample, of subjects with childhood-onset schizophrenia, the increase in genomic disruptions was twofold over control subjects.

The report represents a collaboration between a team led by Jon McClellan, Tom Walsh, and Marie-Claire King of the University of Washington and Jonathan Sebat and Shane McCarthy of Cold Spring Harbor Laboratory, and a second team led by Judith Rapoport and Anjené Addington of the National Institute of Mental Health. Their results, the authors argue, support the possibility that many cases of schizophrenia can be traced to genetic lesions of single genes, perhaps interacting with environmental factors. This contrasts with the currently popular model, whereby schizophrenia is primarily a disease of many small genetic perturbations contributing to the overall genetic susceptibility of an individual.

Zooming in
Gross chromosomal deletions or duplications are detectable by traditional karyotyping techniques, which were used in the identification of important candidate genes for schizophrenia such as DISC1, PDE4B, and NPAS3 (see Chubb et al., 2008; also see SRF related news story). Similarly, the large-scale deletions of chromosome 22 that underlie 22q11 deletion (velocardiofacial) syndrome have cast suspicions on genes in that region. However, candidate genes have typically been identified at the submicroscopic level, by examining single-nucleotide polymorphisms (SNPs) in association studies. The first CNV map (Redon et al., 2006; also see SRF related news story) indicated that structural variations affect more genomic real estate than SNPs, but until the recent development of microarray-based methods, investigation of the possible pathogenic role of CNVs has been limited.

The new results from Walsh and colleagues complement recent work of the Cardiff group led by Michael Owen and Michael O'Donovan (Kirov et al., 2008). As reported in the February 1 issue of Human Molecular Genetics, first author George Kirov and colleagues identified 13 suspect CNVs in a study of 93 individuals with schizophrenia. They identified two as being very likely to have pathogenic consequences—a 0.25 mb deletion of 2p16.3 that spans the promoter and exon 1 of neurexin 1 (NRXN1) and a duplication on chromosome 15q13.1 that involves three genes, including the gene encoding amyloid precursor-binding protein A2 (APBA2, also known as Mint2). CNV disruption of NRXN1 has also been implicated in mental retardation (Friedman et al., 2006) and autism (Autism Genome Project Consortium, 2007).

In the new paper by first author Walsh and colleagues, the researchers identified structural variations larger than 100 kb. After initial detection of these events in cases and controls, the two teams used high-resolution arrays to validate the events, to eliminate false positive results, and to characterize genomic breakpoints.

The University of Washington/Cold Spring Harbor team studied 150 cases, including 76 cases in which psychotic symptoms emerged before age 18. The researchers found that rare variants that disrupt genes were three times more frequent in cases than in controls (15 percent vs. 5 percent, respectively; p = 0.0008), and four times more frequent (20 percent; p = 0.0001) in the 76 cases where onset was before age 18. They report that they were able to identify 53 microdeletions or duplications previously unreported.

The NIMH team studied their cohort of 83 individuals with childhood-onset schizophrenia (COS), a highly unusual form of the disease that appears before puberty (see SRF related news story). In the COS study, rare CNVs were more than twice as likely in cases as in controls—in this instance, the non-transmitted chromosomes of the COS patients’ parents (28 percent vs. 13 percent; p = 0.03). In this study, 27 new CNVs were reported.

In subsequent pathway analysis, Walsh and colleagues found that genes disrupted by CNVs in the cases they studied were significantly overrepresented in neurodevelopmental pathways, including those involved in neuregulin signaling, ERK/MAPK signaling, long-term potentiation, and axon guidance.

Walsh and colleagues write that their results underscore the need for “a new approach to gene discovery for schizophrenia, and likely for other psychiatric disorders.” In contrast to the dominant common disease/common allele model, which posits that schizophrenia is caused by combinations of common alleles that each contribute a modest effect, they propose that “some mutations predisposing to schizophrenia are highly penetrant, individually rare, and of recent origin, even specific to single cases or families” (see also McClellan et al., 2007).

While acknowledging that the identification of very rare variants cannot conclusively establish causal links to illness by themselves—many are “private,” or restricted to a single individual or family—Walsh and colleagues see microarray-based studies of structural variation as a vital advance in psychiatric genetics. “Any gene harboring a deleterious structural mutation becomes a candidate gene to be screened by other methods for additional, presumably smaller, deleterious mutations in unrelated individuals,” they write. “The underlying hypothesis is that a gene harboring one mutation for an illness is likely to harbor more than one.”—Peter Farley.

Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M, Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand E, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King M-C, Sebat J. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Sciencexpress. 2008 Mar 27. Abstract

Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O'Donovan MC, Erdogan F, Owen MJ, Ropers HH, Ullmann R. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet. 2008 Feb 1;17(3):458-65. Epub 2007 Nov 6. Abstract

Comments on News and Primary Papers
Comment by:  Daniel Weinberger, SRF Advisor
Submitted 27 March 2008 Posted 27 March 2008

The paper by Walsh et al. is an important addition to the expanding literature on copy number variations in the human genome and their potential role in causing neuropsychiatric disorders. It is clear that copy number variations are important aspects of human genetic variation and that deletions and duplications in diverse genes throughout the genome are likely to affect the function of these genes and possibly the development and function of the human brain. So-called private variations, such as those described in this paper, i.e., changes in the genome found in only a single individual, as all of these variations are, are difficult to establish as pathogenic factors, because it is hard to know how much they contribute to the complex problem of human behavioral variation in a single individual. If the change is private, i.e., only in one case and not enriched in cases as a group, as are common genetic polymorphisms such as SNPs, how much they account for case status is very difficult to prove.

An assumption implicit in this paper is that these private variations may be...  Read more

View all comments by Daniel Weinberger

Comment by:  William Honer
Submitted 28 March 2008 Posted 28 March 2008
  I recommend the Primary Papers

As new technologies are applied to understanding the etiology and pathophysiology of schizophrenia, considering the clinical features of the cases studied and the implications of the findings is of value. The conclusion of the Walsh et al. paper, “these results suggest that schizophrenia can be caused by rare mutations….“ is worth considering carefully.

What evidence is needed to link an observation in the laboratory or clinic to cause? Recent recommendations for the content of papers in epidemiology (von Elm et al., 2008) remind us of the suggestions of A.V. Hill (Hill, 1965). To discern the implications of a finding, or association, for causality, Hill suggests assessment of the following:

1. Strength of the association: this is not the observed p-value, but a measure of the magnitude of the association. In the Walsh et al. study, the primary outcome measure, structural variants duplicating or deleting genes was observed in 15 percent of cases, and 5 percent of controls. But...  Read more

View all comments by William Honer

Comment by:  Todd LenczAnil Malhotra (SRF Advisor)
Submitted 30 March 2008 Posted 30 March 2008

The new study by Walsh et al. (2008), as well as recent data from other groups working in schizophrenia, autism, and mental retardation, make a strong case for including copy number variants as an important source of risk for neurodevelopmental phenotypes. These findings raise several intriguing new questions for future research, including: the degree of causality/penetrance that can be attributed to individual CNVs; diagnostic specificity; and recency of their origins. While these questions are difficult to address in the context of private mutations, one potential source of additional information is the examination of common, recurrent CNVs, which have not yet been systematically studied as potential risk factors for schizophrenia.

Still, the association of rare CNVs with schizophrenia provides additional evidence that genetic transmission patterns may be a complex hybrid of common, low-penetrant alleles and rare, highly penetrant variants. In diseases ranging from Parkinson's to colon cancer, the literature demonstrates that rare penetrant loci are...  Read more

View all comments by Todd Lencz
View all comments by Anil Malhotra

Comment by:  Ben Pickard
Submitted 31 March 2008 Posted 31 March 2008

In my mind, the study of CNVs in autism (and likely soon in schizophrenia/bipolar disorder, which are a little behind) is likely to put biological meat on the bones of illness etiology and finally lay to rest the annoyingly persistent taunts that genetics hasn’t delivered on its promises for psychiatric illness.

I don’t think it’s necessary at the moment to wring our hands at any inconsistencies between the Walsh et al. and previous studies of CNV in schizophrenia (e.g., Kirov et al., 2008). There are a number of factors which I think are going to influence the frequency, type, and identity of CNVs found in any given study.

1. CNVs are going to be found at the rare/penetrant/familial end of the disease allele spectrum—in direct contrast to the common risk variants which are the targets of recent GWAS studies. In the short term, we are likely to see a large number of different CNVs identified. The nature of this spectrum, however, is that there will be more common pathological CNVs which should be replicated sooner—NRXN1, APBA2 (Kirov et al., 2008), CNTNAP2...  Read more

View all comments by Ben Pickard

Comment by:  Christopher RossRussell L. Margolis
Submitted 3 April 2008 Posted 3 April 2008

We agree with the comments of Weinberger, Lencz and Malhotra, and Pickard, and the question raised by Honer about the extent to which the association may be more to mental retardation than schizophrenia. These new studies of copy number variation represent important advances, but need to be interpreted carefully.

We are now getting two different kinds of data on schizophrenia, which can be seen as two opposite poles. The first is from association studies with common variants, in which large numbers of people are required to see significance, and the strengths of the associations are quite modest. These kinds of vulnerability factors would presumably contribute a very modest increase in risk, and many taken together would cause the disease. By contrast, the “private” mutations, as identified by the Sebat study, could potentially be completely causative, but because they are present in only single individuals or very small numbers of individuals, it is difficult to be certain of causality. Furthermore, since some of them in the early-onset schizophrenia patients were...  Read more

View all comments by Christopher Ross
View all comments by Russell L. Margolis

Comment by:  Michael Owen, SRF AdvisorMichael O'Donovan (SRF Advisor)George Kirov
Submitted 15 April 2008 Posted 15 April 2008

The idea that a proportion of schizophrenia is associated with rare chromosomal abnormalities has been around for some time, but it has been difficult to be sure whether such events are pathogenic given that most are rare. Two instances where a pathogenic role seems likely are first, the balanced ch1:11 translocation that breaks DISC1, where pathogenesis seems likely due to co-segregation with disease in a large family, and second, deletion of chromosome 22q11, which is sufficiently common for rates of psychosis to be compared with that in the general population. This association came to light because of the recognizable physical phenotype associated with deletion of 22q11, and the field has been waiting for the availability of genome-wide detection methods that would allow the identification of other sub-microscopic chromosomal abnormalities that might be involved, but whose presence is not predicted by non-psychiatric syndromal features. This technology is now upon us in the form of various microarray-based methods, and we can expect a slew of studies addressing this...  Read more

View all comments by Michael Owen
View all comments by Michael O'Donovan
View all comments by George Kirov

Comment by:  Ridha JooberPatricia Boksa
Submitted 2 May 2008 Posted 4 May 2008

Walsh et al. claim that rare and severe chromosomal structural variants (SVs) (i.e., not described in the literature or in the specialized databases as of November 2007) are highly penetrant events each explaining a few, if not singular, cases of schizophrenia.

However, their definition of rareness is questionable. Indeed, it is unclear why SVs that are rare (<1 percent) but previously described should be omitted from their analysis. In addition, contrary to their own definition of rareness, the authors included in the COS sample several SVs that have been previously mentioned in the literature (e.g. “115 kb deletion on chromosome 2p16.3 disrupting NRXN1”). Furthermore, some of these SVs (entire Y chromosome duplication) are certainly not rare (by the authors’ definition), nor highly penetrant with regard to psychosis (Price et al., 1967). Finally, as their definition of rareness depends on a specific date, the results of this study will change over time.

As to the assessment of...  Read more

View all comments by Ridha Joober
View all comments by Patricia Boksa
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