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S.4.06 An association study of dopaminergic genes in a sample of 283 Dutch schizophrenic patients
Schizophrenia: towards new drug targets NAA concentrations were significantly decreased in the temporal cortex in rats reared in isolation when compared to socially housed controls (p<0.01 vs. controls). However NAA concentrations were not significantly different from controls in any of the other regions investigated (i.e. frontal cortex, hippocampus or the caudate/putamen) (Table 1). Table 1: NAA concentrations (nmoles/mg protein) in brain regions of rats reared in isolation and in their socially housed controls Region
Social
Isolates
Temporal Cortex Frontal Cortex Hippocampus Caudate/Putamen
85.83±18.67 88.73±13.89 91.43±22.94 70.56±6.76
73.17±9.21** 86.22±13.29 96.35±10.76 68.94±6.60
Levels are shown as Mean±SEM with n=27 for controls and 28 for isolates. ** p<0.01 vs. control.
These results indicate a disturbance of neuronal function reflected by NAA reductions in the temporal cortex in isolation reared rats, equivalent to the regional specificity of the NAA deficit in schizophrenia [2], providing further evidence that isolation rearing can mimic aspects of the neuronal pathology of schizophrenia. References [1] Demougeot, C., Garnier, P., Mossiat, C., Bertrand, N., Giroud, M., Beley, A. and Marie, C., N-acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury. J. Neurochem. 77 (2001), pp. 408–415. [2] Nudmamud, S., Reynolds, L.M. and Reynolds, G.P., N-acetylaspartate and N-acetylaspartylglutamate deficits in superior temporal cortex in schizophrenia and bipolar disorder. Biol. Psychiatry 53 (2003), pp.1138–1141. P.4.06 An association study of dopaminergic genes in a sample of 283 Dutch schizophrenic patients M.L.C. Hoogendoorn, S.C. Bakker, H.G. Schnack, H.G. Otten, J.P.C. Selten, P.L. Pearson, R.J. Sinke, R.S. Kahn. Department of Psychiatry, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Genes involved in dopamine neurotransmission have been suggested to contribute to the development of schizophrenia. However, reported associations of the disorder with genetic markers close to or within dopaminergic genes have shown inconsistent results.
S67
Possible explanations are differences in phenotyping, genetic heterogeneity, low marker informativity, the use of sample sizes with insufficient power. Here, we present an association study of seven genes involved in dopamine synthesis, transport and degradation and four dopamine receptor genes in a large sample of Dutch schizophrenic patients. The initial sample consisted of 208 schizophrenic patients and 288 unmatched control individuals. To reduce genetic heterogeneity, only patients with at least 3 Caucasian grandparents of Dutch ancestry were ascertained. A DSM-IV diagnosis of schizophrenia was made using the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen et al., 1992) and additional information from medical records and clinicians of the patients. All patients were diagnosed by well-trained raters. Initially, for the efficient screening of multiple microsatellite markers, a DNA pooling technique was used that derives allele frequencies from pool patterns, after correction for PCR-induced stutter (for correction procedure see Schnack et al., submitted for publication). For each of the genes, preferably more than one microsatellite marker was selected, either intragenic or close to the gene. Where necessary, polymorphic microsatellite markers were identified using information from the human genome sequence databases. For each marker, a c2 -test was used to compare allele frequencies between the patients and the controls. Significantly different allele frequencies were found for three markers close to or within the DRD5 receptor gene (p=0.04, p=0.003 and p=0.001, all p-values are two-tailed). In an extended sample of 283 schizophrenic patients and 585 unmatched and unrelated controls, we are currently genotyping these, and additional markers individually. This approach of individual genotyping allows the study of association with subtypes within the group of cases. Both the results of the pooled association study and of individual genotyping in a large Dutch sample of schizophrenic patients will contribute to the understanding of the involvement of dopaminergic genes in the disorder; which in turn may lead to more effective therapy.
References [1] Andreasen, N.C., Flaum, M., Arndt, S., 1992. The comprehensive assessment of symptoms and history (CASH): An instrument for assessing psychopathology and diagnosis. Arch. Gen. Psychiatry 49, 615– 623. [2] Schnack, H.G., Bakker, S.C., van ’t Slot, R., Groot, B.M., Sinke R.J., Kahn, R.S., Pearson, P.L.: Accurate Determination of Microsatellite Allele Frequencies in Pooled DNA Samples (submitted for publication)
Social
Isolates
Temporal Cortex Frontal Cortex Hippocampus Caudate/Putamen
85.83±18.67 88.73±13.89 91.43±22.94 70.56±6.76
73.17±9.21** 86.22±13.29 96.35±10.76 68.94±6.60
Levels are shown as Mean±SEM with n=27 for controls and 28 for isolates. ** p<0.01 vs. control.
These results indicate a disturbance of neuronal function reflected by NAA reductions in the temporal cortex in isolation reared rats, equivalent to the regional specificity of the NAA deficit in schizophrenia [2], providing further evidence that isolation rearing can mimic aspects of the neuronal pathology of schizophrenia. References [1] Demougeot, C., Garnier, P., Mossiat, C., Bertrand, N., Giroud, M., Beley, A. and Marie, C., N-acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury. J. Neurochem. 77 (2001), pp. 408–415. [2] Nudmamud, S., Reynolds, L.M. and Reynolds, G.P., N-acetylaspartate and N-acetylaspartylglutamate deficits in superior temporal cortex in schizophrenia and bipolar disorder. Biol. Psychiatry 53 (2003), pp.1138–1141. P.4.06 An association study of dopaminergic genes in a sample of 283 Dutch schizophrenic patients M.L.C. Hoogendoorn, S.C. Bakker, H.G. Schnack, H.G. Otten, J.P.C. Selten, P.L. Pearson, R.J. Sinke, R.S. Kahn. Department of Psychiatry, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands Genes involved in dopamine neurotransmission have been suggested to contribute to the development of schizophrenia. However, reported associations of the disorder with genetic markers close to or within dopaminergic genes have shown inconsistent results.
S67
Possible explanations are differences in phenotyping, genetic heterogeneity, low marker informativity, the use of sample sizes with insufficient power. Here, we present an association study of seven genes involved in dopamine synthesis, transport and degradation and four dopamine receptor genes in a large sample of Dutch schizophrenic patients. The initial sample consisted of 208 schizophrenic patients and 288 unmatched control individuals. To reduce genetic heterogeneity, only patients with at least 3 Caucasian grandparents of Dutch ancestry were ascertained. A DSM-IV diagnosis of schizophrenia was made using the Comprehensive Assessment of Symptoms and History (CASH) (Andreasen et al., 1992) and additional information from medical records and clinicians of the patients. All patients were diagnosed by well-trained raters. Initially, for the efficient screening of multiple microsatellite markers, a DNA pooling technique was used that derives allele frequencies from pool patterns, after correction for PCR-induced stutter (for correction procedure see Schnack et al., submitted for publication). For each of the genes, preferably more than one microsatellite marker was selected, either intragenic or close to the gene. Where necessary, polymorphic microsatellite markers were identified using information from the human genome sequence databases. For each marker, a c2 -test was used to compare allele frequencies between the patients and the controls. Significantly different allele frequencies were found for three markers close to or within the DRD5 receptor gene (p=0.04, p=0.003 and p=0.001, all p-values are two-tailed). In an extended sample of 283 schizophrenic patients and 585 unmatched and unrelated controls, we are currently genotyping these, and additional markers individually. This approach of individual genotyping allows the study of association with subtypes within the group of cases. Both the results of the pooled association study and of individual genotyping in a large Dutch sample of schizophrenic patients will contribute to the understanding of the involvement of dopaminergic genes in the disorder; which in turn may lead to more effective therapy.
References [1] Andreasen, N.C., Flaum, M., Arndt, S., 1992. The comprehensive assessment of symptoms and history (CASH): An instrument for assessing psychopathology and diagnosis. Arch. Gen. Psychiatry 49, 615– 623. [2] Schnack, H.G., Bakker, S.C., van ’t Slot, R., Groot, B.M., Sinke R.J., Kahn, R.S., Pearson, P.L.: Accurate Determination of Microsatellite Allele Frequencies in Pooled DNA Samples (submitted for publication)