As part of our ongoing coverage of the 2011 International Congress on Schizophrenia Research (ICOSR), held 2-6 April in Colorado Springs, Colorado, we bring you session summaries from some of the attendees. For this report, we thank Allison A. Curley of the University of Pittsburgh, Pennsylvania.
5 May 2011. It is widely accepted that genetics contributes significantly to the etiology of schizophrenia, with heritability estimates around 80 percent (Cardno and Gottesman, 2000). With many recent developments in the field of genetics, there has been an explosion of research examining genetic variants underlying schizophrenia. To date, however, the effects of the identified variants have been disappointingly small, and unable to account for such high heritability of the illness. This has left researchers wondering just where exactly this “missing heritability” is (Maher, 2008). In the Wednesday, April 6, afternoon session entitled, "Recent Findings in the Genetics of Schizophrenia," chaired by Gunvant Thaker of the University of Maryland in Baltimore, the talks highlighted a number of studies aimed at finding these missing genes. Broadly, the work fell into two major categories: genetic association studies using endophenotypes, and genomewide association studies (GWAS) comparing the control and schizophrenia genomes.
The first speaker was Nithin Krishna from the University of Maryland, who discussed his work identifying a novel risk gene using smooth pursuit eye movement as a schizophrenia endophenotype. Krishna demonstrated that a single nucleotide polymorphism (SNP) for ALDH5A1, which codes for succinic semi-aldehyde dehydrogenase, an enzyme involved in GABA metabolism, is associated with poor smooth pursuit eye movements and abnormal early visual and motion processing.
Alan Sanders from the NorthShore University HealthSystem in Evanston, Illinois, discussed a genomewide mRNA expression study using lymphoblastoid cell lines (LCLs) from schizophrenia patients and control subjects. Sanders reported that the most significant findings were in the major histocompatibility complex (MHC) region of chromosome 6, with over 18 histone genes that were significantly downregulated in schizophrenia. The MHC region has been identified in a previous GWAS study (Shi et al., 2009). Importantly, this study confirms that LCLs can be utilized to detect differential expression in schizophrenia.
The third speaker was David Glahn from Yale University, New Haven, Connecticut, who discussed an alternative strategy to examine genetic risk in schizophrenia. Using a meta-analysis of voxel-based morphometry studies (Glahn et al., 2008), Glahn identified a network of brain regions with reduced gray matter volume in schizophrenia, and then determined the heritability of the network in a healthy control population. Although a GWAS failed to identify a genomewide significant quantitative trait locus (QTL) for the network, a significant SNP in the DPP6 gene was identified for superior temporal gyrus thickness. These findings implicate DPP6, involved in potassium channel signaling, as a novel schizophrenia risk gene candidate.
Thomas Wassink of the University of Iowa in Iowa City presented his findings on a SNP in the zinc finger gene ZNF804A, which has previously been associated with schizophrenia using GWAS (O’Donovan et al., 2008), and with increased white matter volume in control subjects (Lencz et al., 2010). Wassink demonstrated that this risk allele was associated with increased cortical white matter volume in both control and schizophrenia subjects, and with more severe psychotic symptoms in the latter group. These data demonstrate a phenotypic profile that is associated with the ZNF804A risk allele.
Todd Lencz of the Zucker Hillside Hospital in Glen Oaks, New York, presented data from a GWAS performed in a large and ethnically homogeneous Ashkenazi Jewish cohort. Lencz identified one intergenic SNP that was significant at the genomewide level, located near NDST3, the gene that encodes heparan glucosaminyl. This enzyme partially determines the binding properties of heparan sulfate, an extracellular matrix protein that is part of the neuregulin/ErbB4 pathway dysregulated in schizophrenia.
Rachel Wallwork of the National Institute of Mental Health (NIMH), Bethesda, Maryland, discussed evidence implicating the kynurenine pathway of tryptophan degradation in cognitive deficits in schizophrenia, and found several modest associations between pathway genes and cognition in a GWAS. Subsequent epistatic analyses identified several interactions between SNPs from kynurenine pathway genes KAT2, KYNU, and KMO. Wallwork concluded by suggesting that drugs targeting this pathway may exhibit cognition-enhancing effects.
In a departure from the rest of the symposium, Brooke Miller of Scripps Florida in Jupiter concluded with a study of microRNAs in schizophrenia. Using prefrontal cortical tissue from control and schizophrenia subjects, Miller identified a dysregulation in the microRNA miR-132 in schizophrenia. Subsequent pathway analyses of miR-132 targets revealed that a number were upregulated in schizophrenia. These data are especially interesting, given the role of miR-132 in NMDA signaling, which is thought to be reduced in schizophrenia (Miller and Wahlestedt, 2010).
In summary, this symposium highlighted several recent findings in the genetics of schizophrenia. Genetic association studies identified genes involved in GABA metabolism and potassium channel signaling, as well as a zinc finger gene of unknown function, as underlying schizophrenia endophenotypes. GWAS studies identified the MHC region of chromosome 6, the neuregulin/ErbB4 and kynurenine pathways, and targets of the miRNA miR-132 as genes that are differentially expressed in schizophrenia. With the potential for gene variants to greatly inform therapeutic strategies in schizophrenia, the hot pursuit of the genetic culprits of schizophrenia is definitely a story to follow.—Allison A. Curley.