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ICOSR 2007—Researchers Report from "Beyond Candidate Genes"

Editor's Note: On Thursday, 29 March 2007, the first full day of the International Congress on Schizophrenia Research in Colorado Springs, Anil Malhotra of Zucker Hillside Hospital in Glen Oaks, New York, chaired a session entitled, "Beyond candidate genes: new approaches to the identification of schizophrenia susceptibility loci." We are grateful to Eric Epping of the University of Iowa, one of the Young Investigator travel awardees to the meeting, who filed the following report.

11 April 2007. Joel Kleinman from the National Institute of Mental Health in Bethesda, Maryland, kicked off the symposium, presenting data on the identification and characterization of a novel schizophrenia susceptibility gene, KCNH2, a voltage-gated potassium channel. This gene candidate was identified from microarray expression studies, with follow-up work from a family-based association screen (NIMH Sibling Study), and further confirmation in additional datasets. Located on chromosome 7q, the gene encodes a protein involved in slow repolarization of the action potential in heart muscle and is involved in regulating the QT interval. Risk alleles were found to be associated with processing speed, IQ, visual memory, and reduced hippocampal volume in healthy subjects. In a postmortem brain collection, full length KCNH2 mRNA levels were reduced in subjects with schizophrenia compared to controls, and expression of a novel shorter isoform was increased. Functional properties of the isoforms were characterized in cell culture, indicating differences in channel activity. Antipsychotics also bind to the channel and inhibit its activity, although no frontal cortex changes in a rat model exposed to antipsychotics were found.

In his talk entitled “Transgenic manipulations of putative susceptibility genes,” Tyrone Cannon from the University of California, Los Angeles, described a novel mouse model of DISC1 that his group has used to elucidate functional effects of mutations in this gene. Using an inducible transgene expressing a variant of DISC1 that disrupts normal DISC1 binding to NUDEL and LIS1, the researchers found decreased performance in working memory in adult animals that had the transgene expressed at postnatal day (PND) 7. This effect on working memory was not seen in transgenic animals in whom the DISC1 variant was expressed in adulthood. PND7-induced animals also had worse performance on the forced swim test and reduced sociability. At the cellular level, the PND7-induced animals showed reduced dendritic arborization and reduced synaptic transmission. This model allows the researchers to test hypotheses about the effects of DISC1 variants at the molecular and whole animal level, and has shown that the effects are time-specific in development.

Using DNA chips capable of genotyping nearly 500,000 (500K) single nucleotide polymorphisms (SNPs), Todd Lencz of Zucker Hillside Hospital presented data on structural genomic variation in schizophrenia. In a search for regions of autozygosity, or segments of the genome with extended shared haplotypes (i.e., clusters of related alleles with the same sequence on both chromosomes), several runs of homozygosity (ROH) were found to be more common in patients with schizophrenia on multiple chromosomes. One gene within a ROH more frequent in schizophrenia includes the CAPON gene, which competes with PSD95 (a post-synaptic protein in NMDA neurons) for binding to neuronal nitric oxide synthase. These regions may indicate areas of low recombination or evolutionary selection. This technique also identifies regions of chromosomal copy number variation, which can be identified by measuring signal intensities on the SNP chips. Their initial analyses, according to Lencz, indicate that the ROH results are not primarily driven by copy number variation.

Anil Malhotra also presented results from a whole genome analysis of the SNP array data, which found an association with variants in a region containing the genes for two cytokine receptors on a pseudoautosomal region of the X and Y chromosomes (see SRF related news story).—Eric Epping.

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