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.
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