20 December 2011. Looking in a new Bulgarian sample, researchers conducted a study, published online in Molecular Psychiatry on November 15, finding that de novo copy number variations (CNVs) occurred more frequently in schizophrenia patients than in controls. This news, presented earlier this year at the World Congress of Psychiatric Genetics (see SRF related news story), adds to the evidence that the loss or gain of a chromosome segment elevates risk for schizophrenia and other brain disorders (see SRF related news story), and makes a case for de novo CNVs—those spontaneously occurring in germ cells rather than being inherited from parents—as factors behind sporadic cases of schizophrenia.
Led by Michael Owen of Cardiff University in the U.K., the researchers screened 662 individuals with schizophrenia and both parents for CNVs, and turned up 34 de novo events; these were more frequent in cases (5.1 percent) compared to 2,623 controls (2.2 percent). Eight of the de novo CNVs occurred at locations already linked to schizophrenia (3q29, 15q11.2, 15q13.3, and 16p11.2), whereas others landed in new regions and genes, including members of the DLG family found in the post-synaptic density, where they are involved in getting receptors, ion channels, and signaling proteins to their proper locations. Two other CNVs implicated EHMT1, a gene encoding a histone methyltransferase reported to directly regulate DLG members (Kramer et al., 2011).
Undertaking gene-set analysis to get a picture of the kinds of genes affected by these CNVs, the researchers found that CNVs in schizophrenia cases tended to hit genes encoding post-synaptic density proteins more frequently than controls (P = 1.72 x 10-6), with genes for the activity-regulated cytoskeleton-associated protein complex (ARC) and the NMDA receptor complex contributing the bulk of this enrichment. An independent analysis of a large dataset comprising 17,907 cases and 10,585 controls revealed a similar picture, with de novo CNVs landing in NMDA receptor complex genes in schizophrenia more frequently than controls (P = 0.0015). This finding supports the idea that disruptions to NMDA receptor signaling may lay the groundwork for schizophrenia (see SRF Hypothesis).—Michele Solis.
Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, Moran J, Chambert K, Toncheva D, Georgieva L, Grozeva D, Fjodorova M, Wollerton R, Rees E, Nikolov I, van de Lagemaat LN, Bayés A, Fernandez E, Olason PI, Böttcher Y, Komiyama NH, Collins MO, Choudhary J, Stefansson K, Stefansson H, Grant SG, Purcell S, Sklar P, O'Donovan MC, Owen MJ. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2011 Nov 15. Abstract