FIBROBLAST GROWTH FACTORS AND BRAIN VOLUME IN SCHIZOPHRENIA PATIENTS AND HEALTHY CONTROLS

Abstracts

phrenia (p = 0.37). No significant allelic or genotypic association of the plasma IL-10 levels with IL-10 and IL-10R genes was detected. Discussion: The present study confirmed the previous findings of increased levels of IL-6 and IL-10 in schizophrenia. This study further examined, for the first time, the association of plasma IL-6 and IL-10 levels and genetic polymorphisms in schizophrenia. We found no associations of genetic polymorphisms of IL-6 and IL-10 genes with schizophrenia or plasma levels. However, the Asp358 allele of the IL-6R gene was found to be associated with decreased IL-6 levels in the control group, which is consistent with previous studies. A recent study has suggested that the receptor function may be more efficient in the Asp-IL-6R than Ala-IL-6R protein. Taken together, elevated plasma IL-6 levels and excess in the Asp358 allele of the IL-6R may contribute to conferring the risk of developing schizophrenia due to excessive IL-6 signal.

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or 1/2-1/2 (O.R = 0.11) haplotypes presented reduced TD risk. Both haplotypes remain significant after multiple correction procedure. Discussion: Our results implicate GFRA2 polymorphic variants with reduced risk for developing TD in schizophrenia subjects taking antipsychotics. We observed significant power in our sample to detect the positive associations. Ethnic population stratification does not seem to be an important limitation in this study as the results are reproducible if excluded the African-American Background subjects. Several results in the literature relate GDNF signalling pathway with neuroprotective effects in, at least, central dopaminergic neurons and spinal motoneurons. Although there is no reported functionality for the variants evaluated in this study, this study further support an effect of GDNF pathway in neurological conditions. doi:10.1016/j.schres.2010.02.843

doi:10.1016/j.schres.2010.02.842

Poster 83 Poster 82 GLIAL CELL LINE–DERIVED NEUROTROPHIC FACTOR RECEPTOR ALPHA 2 IS ASSOCIATED WITH TARDIVE DYSKINESIA Renan P. Souza1,2,3,4, Gary Remington1,2, Herbert Y. Meltzer5, Jeffrey A. Lieberman6, Steve G. Potkin7, James L. Kennedy1,2, Albert H. Wong1,4 1 Neurogenetics Section, Centre for Addiction and Mental Health Toronto, Ontario, Canada; 2Department of Psychiatry, University of Toronto Toronto, Ontario, Canada; 3Departamento de Saude Mental, Universidade Federal de Minas Gerais Belo Horizonte, Minas Gerais, Brazil; 4Department of Pharmacology, University of Toronto Toronto, Ontario, Canada; 5 Psychiatric Hospital, Vanderbilt University Nashville, Tennessee, USA; 6 New York State Psychiatric Institute, Columbia University Medical Centre New York City, New York, USA; 7Brain Imaging Center, University of California Irvine, California, USA Background: A major hypothesis is that tardive dyskinesia (TD) is a pharmacogenetic disease presenting interaction of conventional antipsychotic exposure with individual genetic variation mediates risk. Several results in the literature relate glial cell line–derived neurotrophic factor (GDNF) signalling pathway with neuroprotective effects in, at least, central dopaminergic neurons and spinal motoneurons. Considering evidences of GDNF effect on Parkinson's disease and dopaminergic neuron survival as well as GDNF alpha-receptor 2 (GFRA2) molecular findings, we hypothesized that variants in GFRA2 gene could play a role in the genetic susceptibility of TD. Methods: Local Ethics Committees have approved this protocol and Consent Form was obtained from all subjects. Two hundred and sixteen subjects were recruited from the Centre for Addiction and Mental Health, Case Western Reserve and the Hillside Hospital. All subjects presented Caucasian ethnic Background excluding 16 subjects from Case Western and 38 from the Centre for Addiction and Mental Health that were African-American. All patients had at least 1 year of cumulative treatment with typical antipsychotics. TD was assessed using Abnormal Involuntary Movement Scale (AIMS) or Hillside Simpson Dyskinesia Scale (HSDS) for patients recruited from the Hillside Hospital. We genotyped 16 tag SNPs (table 1) selected among variants presenting frequency higher than 10% in the Caucasian Hap Map population. Results: We observed one significant allelic association (rs4739285, permutated p = 0.035). Heterozygosis for rs10088105 (O.R. = 0.43) and rs6587002 (O.R. = 0.47) showed a protective effect while 1/1 genotype of rs4567028 (O.R. = 3.01) and rs6587002 (O.R. = 1.15) showed a risk effect. Moreover, subjects carrying 2-2 (O.R. = 0.20)

FIBROBLAST GROWTH FACTORS AND BRAIN VOLUME IN SCHIZOPHRENIA PATIENTS AND HEALTHY CONTROLS Afke F. Terwisscha van Schel, Steven C. Bakker, Neeltje E.M. van Haren, Hilleke E. Hulshoff Pol, Wiepke Cahn, Roel A. Ophoff, René S. Kahn University Medical Centre Utrecht, Rudolf Magnus Institute of Neuroscience Utrecht Netherlands Background: There is convincing evidence for an involvement of fibroblast growth factors (FGFs) in schizophrenia (Terwisscha van Scheltinga et al., 2009). FGFs regulate growth, maintenance and repair of neuronal tissue. This makes the genes in the FGF system plausible candidate genes for the smaller brain volume seen in schizophrenia patients and their relatives relative to control subjects. We use total brain volume as an endophenotype of schizophrenia, since it has a 90% heritability, can be reliably measured, cosegregates with illness in families and is relatively independent of clinical state (van Haren et al., 2008). Methods: Using online genomic databases 1231 SNPs in 22 FGFs, 5 FGF receptors and 56 interacting genes were selected and genotyped using the Illumina HumanHap550 beadchip. A 1.5T MRI scan of the brain was acquired for 169 schizophrenia cases and 159 healthy controls. Total brain volume was estimated and corrected for age, sex and intracranial volume. A linear regression analysis was performed, using disease status as an independent variable. Results: There were significantly more males in the patient group than in the control group (80 v. 54% male, p < 0.0001) and the unstanderdised residual of brain volume corrected for age, sex and intracranial volume was significantly lower in the patient group (11.0 v. 11.7, p < 0.0001). FGF14 SNPs are overrepresented in the list of highest main effects (brain volume regardless of disease status). From this large gene we used 91 SNPs. It has previously been implicated in movement disorders in mice. In the list of highest interaction effects (brain volume difference in patients) 3 out of 5 SNPs are related to platelet derived growth factor function (PDGFRA, PDGFRB and adaptor protein SHB). Discussion: After correction for 83 genes several trends are noticeable, but no significant results were found. Although this is a relatively large sample of genotyped subjects with MRI scans, we cannot draw firm conclusions. Therefore a replication of the top SNPs in an independent sample is needed to determine the effects of FGF genes on brain volume in schizophrenia patients and controls. doi:10.1016/j.schres.2010.02.844