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Copy Number Variants in Schizophrenia Converge on the Synapse

4 June 2010. A new study fingers a diverse array of copy number variants (CNVs)—duplications or deletions of DNA—in schizophrenia. According to the report published online in PNAS on May 20, many of these CNVs disrupt genes involved in synaptic transmission.

The results put the spotlight on the interacting network of molecules that contribute to communication between neurons, and suggest that problems with any one of these molecules may disrupt brain signaling and confer susceptibility to schizophrenia. Although previous studies of schizophrenia have turned up genes for individual synaptic proteins (see SRF related news story), the new findings seem particularly enriched for neuronal signaling genes.

"Most of the interesting genes that came up had something to do with synaptic function or transmission or signaling in the brain," said senior author Hakon Hakonarson of the Children's Hospital of Philadelphia (CHOP).

Though not the first to look for CNVs in schizophrenia (see SRF related news story), the study is one of the most thorough, using a Affymetrix 6.0 gene chip that probed over 900,000 regions of the genome for deletions or duplications and over 900,000 single nucleotide polymorphisms (SNPs). This high-resolution search revealed CNVs large and small—including many under 100 kb, which have been overlooked in previous studies.

Make it a combo
First author Joseph Glessner and colleagues at CHOP combined their samples from patients and controls with those from collaborators at Mt. Sinai School of Medicine and the University of Pennsylvania to assemble the needed samples. They also included a substantial amount of data from samples that had already been genotyped with the same chip and deposited into the database of Genotype and Phenotype (dbGaP)—but whose CNVs had not yet been analyzed (O'Donovan et al., 2008). This resulted in a total of 1,735 schizophrenia samples and 3,485 controls, which were divided into a discovery and replication group.

The researchers detected CNVs in both cases and controls, and some of these CNVs overlapped in the same genome regions. Deletions or duplications in eight of these CNV-containing regions were associated with schizophrenia in both the discovery and replication cohorts. While CNVs in five of these regions occurred nearly exclusively in schizophrenia cases, with a frequency of less than 0.25 percent among controls, CNVs in the other three regions were more common, but still occurred more frequently in schizophrenia cases.

The CNVs landed either within genes, or within striking distance, where they may still do some damage to regulatory regions of the nearby gene. Of the many genes impacted by these CNVs, four were particularly interesting. CACNA1B, which encodes a subunit of a calcium channel involved in neurotransmitter release, has been associated with schizophrenia (Moskvina et al., 2009), as has its cousin, CACNA1C, which has achieved significance in a genomewide association study of bipolar disorder (see SRF related news story), and in a combined schizophrenia/bipolar sample reported at the World Congress on Psychiatric Genetics last fall (see SRF related conference story).

Other featured genes were DOC2A, which encodes a calcium sensor involved in neurotransmitter release, and RET and RIT2, Ras-related genes important for neural development and signal transduction within cells. Though Ras is best known as a tumor suppressor, studies have uncovered a role for these small GTPases in coupling calcium signals to synaptic plasticity (Finkbeiner et al., 1996).

Other genes in the study's haul included PDPR, which regulates glucose metabolism in the brain, genes related to mitochondria function, and the more familiar COMT, which controls catecholamine neurotransmitter levels.

Focus on function
To help make sense of the jumble of genes impacted by CNVs in the schizophrenia samples, the researchers investigated whether their genes belonged to any particular functional pathway. The bioinformatics tool DAVID indicated that the CNVs tended to affect genes involved in synaptic transmission.

This lends support to proposals that the myriad genes disrupted in schizophrenia have neuronal communication in common. A problem with any one component of the complicated network of molecules involved in passing signals from one neuron to the next may distort the flow of information in the brain and result in symptoms of schizophrenia. This means individuals with schizophrenia could have different genetic reasons for the disorder—a tidy solution to the ever-expanding list of genes associated with schizophrenia. "So each individual one is rare, but when you put them all together, they actually make up quite a significant component of schizophrenia," Hakonarson said.

The researchers plan to sequence the genes turned up in this study in other individuals with schizophrenia in order to identify new variants that their current methods aren't picking up. Finding multiple variants in multiple genes would swell the potential genetic reasons for schizophrenia.—Michele Solis.

Glessner JT, Reilly MP, Kim CE, Takahashi N, Albano A, Hou C, Bradfield JP, Zhang H, Sleiman PM, Flory JH, Imielinski M, Frackelton EC, Chiavacci R, Thomas KA, Garris M, Otieno FG, Davidson M, Weiser M, Reichenberg A, Davis KL, Friedman JI, Cappola TP, Margulies KB, Rader DJ, Grant SF, Buxbaum JD, Gur RE, Hakonarson H. Strong synaptic transmission impact by copy number variations in schizophrenia. Proc Natl Acad Sci U S A. 2010 May 20. Abstract

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