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Copy Number Variants and Schizophrenia

Rare CNVs may be implicated in some cases of sporadic schizophrenia.

Approximately 12% of the human genome consists of relatively common copy number variations (CNVs) — i.e., insertions or duplications of DNA sequences (JW Psychiatry Jan 22 2007). Rare CNVs, however, might be associated with some diseases — e.g., autism. Two research groups have now investigated rare CNVs in schizophrenia patients.

Walsh et al. genotyped two study populations. In 150 adults with sporadic or familial schizophrenia, the researchers found a significantly greater risk for rare CNVs than in matched healthy controls. The researchers found an even higher risk for rare CNVs in a group of 83 youths with childhood-onset schizophrenia and no major chromosomal anomalies, compared with 154 of their parents. The frequency of common CNVs did not differ significantly between adult patients and controls. Compared with the rare CNVs found in controls, those in the schizophrenia patients more frequently disrupted gene structure, and these were significantly overrepresented in neurodevelopmental, RNA, and glutamate pathways.

Xu et al. genotyped a sporadic-schizophrenia cohort (152 adults with sporadic schizophrenia and their unaffected parents) and a familial-schizophrenia cohort (48 parent-child trios where a close relative also had schizophrenia). Controls were 159 healthy volunteers from the community and their parents. Again, rare CNVs were significantly more frequent in the schizophrenia cohorts than in the control group and more frequent in the sporadic cohort than in the familial cohort. Some of the rare CNVs were found in unaffected parents in the control and sporadic-schizophrenia groups.

Comment: Previously, researchers into the genetics of schizophrenia tested common disease–common allele theories in genome-wide and candidate gene association studies, such as those on neuregulin. The current findings extend the heterogeneity of schizophrenia pathogenesis to include rare CNVs. These are highly associated with sporadic schizophrenia. As these genetic complexities unfold, opportunities for developing targeted preventions or interventions will abound.

— Barbara Geller, MD

Published in Journal Watch Psychiatry June 23, 2008

Citation(s):

Walsh T et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008 Apr 25; 320:539.

• Original article (Subscription may be required)
• Medline abstract (Free)

Xu B et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008 May 30; [e-pub ahead of print] (http://dx.doi.org/10.1038/ng.162)