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Analysis of muscarinic 1 promoter polymorphisms on receptor expression and outcome to atypical antipsychotic treatment
7. Genetics, Clinical
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schizophrenia patients. We found that PARS cannot be explained by delayed childbearing by fathers with genetic schizophrenia vulnerability, since paternal age is ~5 years greater in sporadic than in familial schizophrenia cases (33.9 +/-8.5 vs. 28.3 +/-5.5 years : t=-2.41, df=75,p=. 016). We then narrowly defined PARS as sporadic cases with paternal age > 35 and compared them to highly familial cases. This analysis revealed a specific pattern for PARS cases. PARS had superior WAIS-R intelligence scores than the other patients, differing significantly in full scale (90 +/-13 vs. 81 4-/-11 : t=2.4, dr=43, p=.02), verbal (95 +/-14 vs. 85 +/-11 : t= 2.4, df=43, p=.02), performance IQ (84 +/- 10 vs. 77 +/- 12 : t=2.1, df=43, p=.04). The PARS group had a normal verbal IQ with a verbal-performance IQ decrement. PARS patients also performed significantly better in aspects of executive functioning, suggestive of better focused effort (verbal fluency: 18.2 +/-5.8 vs. 14.6 +/-5.1 : t=2.4, df:50, p=.02), perceptual organization (picture arrangement: 7.2 +/-1.8 vs. 5.8 +/-2.2 : t=3.0, df=45, p=.004) and processing speed (digit symbol 6.7 +/-2.9 vs. 5.1 +/-2.4 : t=2.1, df=43, p=.04). In contrast, PARS patients had significantly worse medication free symptoms and eye tracking scores and showed significantly less prefrontal metabolism on a functional imaging paradigm. Taken together these findings are consistent with the hypothesis that PARS patients can be phenotyped by a specific pathophysiology.
ANALYSIS OF MUSCARINIC l PROMOTER POLYMORPHISMS ON RECEPTOR EXPRESSION AND OUTCOME TO ATYPICAL ANTIPSYCHOTIC TREATMENT D. T. Mancama,* I. Mata, J. Munro, S. Osborne, M. J. Arranz, R. K e r w i n
Psychological Medicine, Institute of Psychiatr); London, England, United Kingdom The muscarinic acetylcholine 1 (CHRM 1) receptor is ubiquitously expressed throughout the brain, with high densities found in those cortical and limbic regions thought to be important to the etiology of schizophrenia. Significant reductions in CHRM1 receptor density have been demonstrated in these regions amongst patients, and in this study we report comparable decreases in the levels of steady state frontal cortical CHRMI mRNA expressed in such individuals (F= 6.3, p=0.005). We have examined putative CHRM1 promoter sequences for genetic alterations that may be important to normal gene expression and, of those discovered, have identified significant association between a Tsp45I polymorphism and levels of receptor mRNA. Increased muscarinic activity has been proposed to exert a protective influence on the emergence of positive symptoms in schizophrenia, while a decrease in activity may impart an increase in positive symptoms. To investigate this potential, we have examined the CHRM 1 polymorphisms in olanzapine treated patients prospectively rated for response according to PANSS and GAF. We have also investigated the potential influence of these polymorphisms on outcome to clozapine treatment. No association however has been observed between genotype at the Tsp45I polymorphism and improvement in either positive or negative symptoms during treatment (significance p=0.75; p=0.58 respectively). Similarly no association has been found between the promoter polymorphisms and overall response to clozapine and olanzapine. Our results suggest that CHRM1 promoter polymorphisms do not appear to influence outcome to clozapine or olanzapine treatment, though they may be more relevant to the expression of this receptor in frontal cortical tissue.
GLUTAMATE RECEPTOR GENE (GRIN 1, GRIN2B) 1N SCHIZOPHRENIA: TDT AND CASECONTROLS ANALYSES L. Martucci,* A. C. Wong, J. Trakalo, T. Cate-Carter, E Ajmar, E. Di Maria, E Mandich, E Macciardi, J. L. Kennedy Neurogenetics, Centre for Addiction and Mental Health, Toronto, ON, Canada The etiology of schizophrenia remains unknown although many hypotheses have been formulated. For several years considerable interest has focused on the possible role of glutamate in schizophrenia: the N-Methyl-D-Aspartate Glutamate receptors (NMDAR) play critical roles in excitatory synaptic transmission, plasticity and excitotoxicity in the CNS, and act as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine and GABA. It has been suggested that a weakened glutamatergic tone increase the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. NMDAR functional properties are determined by subunit composition. NR1 is the only subunit that is expressed in all NMDA receptors. The NR2B subunit is equipped with an unusually long carboxyl-terminal domain that is believed to extend into the cytoplasm. Several lines of evidence suggest that this plays a crucial role in cellular signal transduetion. We focused on the study of two polymorphisms in the NR1 subunit gene (GRIND, and of one polymorphism on the NR2B subunit gene (GRIN2B): GRIN 1/1 is a C/G substitution localized on the 5' untranslated region (UTR); GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1, and GRIN2B is a T/G substitution located on the 3'UTR. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested for the presence of an association between GRIN1, GRIN2B and schizophrenia using a case-control and family-based association strategy. The results are as follows: for the case-control sample: GRIN1/I: chi-square=0.013, p=0.908; GRIN1/10: chi-square=0.544, p=0.461; GR1N2B: chi-square=2.795, p=0.095. For the nuclear families sample: GRINI/1, chi-square=2.19, p=0.14; GRIN1/10, chisquare=l.5, p=0.22. GRIN2B, chi-square=l.19, p=0.2753. Haplotype analyses showed a borderline significant result for the A/G haplotype (chi-square=3.86, p-value=0.049). An analysis of variance was conducted to test the association between specific genotype groups and age at onset. No significant results were observed: GRIN1/1, F[df=2]=0.42, p=0.659; GRIN1/10, F[df=2]=0.16, p=0.853; GRIN2B, F[d=2]=0.01, p=0.987. We are currently enlarging our samples to increase the power of the analyses.
PREMORBID A B N O R M A L I T I E S IN PSYCHOTIC PATIENTS ARE ASSOCIATED WITH SCHIZOTYPY IN THEIR RELATIVES I. Mata,* R C. S h a m , M. Beperet, J. A n ' o n d o , A. Albeniz, R. M. M u r r a y
Psychological Medicine, Institute of Psychiatry, London, United Kingdom Schizotypal personality disorder has come to be regarded as one phenotypic expression of familial-genetic liability to schizophrenia, although most studies have failed to confirm the specificity of schizotypy to categorically defined schizophrenia when relatives of patients with other psychoses are included. Some studies have adressed the issue of resemblance between psychotic symptoms of patients and
International Congress on Schizophrenia Research 2003
85
schizophrenia patients. We found that PARS cannot be explained by delayed childbearing by fathers with genetic schizophrenia vulnerability, since paternal age is ~5 years greater in sporadic than in familial schizophrenia cases (33.9 +/-8.5 vs. 28.3 +/-5.5 years : t=-2.41, df=75,p=. 016). We then narrowly defined PARS as sporadic cases with paternal age > 35 and compared them to highly familial cases. This analysis revealed a specific pattern for PARS cases. PARS had superior WAIS-R intelligence scores than the other patients, differing significantly in full scale (90 +/-13 vs. 81 4-/-11 : t=2.4, dr=43, p=.02), verbal (95 +/-14 vs. 85 +/-11 : t= 2.4, df=43, p=.02), performance IQ (84 +/- 10 vs. 77 +/- 12 : t=2.1, df=43, p=.04). The PARS group had a normal verbal IQ with a verbal-performance IQ decrement. PARS patients also performed significantly better in aspects of executive functioning, suggestive of better focused effort (verbal fluency: 18.2 +/-5.8 vs. 14.6 +/-5.1 : t=2.4, df:50, p=.02), perceptual organization (picture arrangement: 7.2 +/-1.8 vs. 5.8 +/-2.2 : t=3.0, df=45, p=.004) and processing speed (digit symbol 6.7 +/-2.9 vs. 5.1 +/-2.4 : t=2.1, df=43, p=.04). In contrast, PARS patients had significantly worse medication free symptoms and eye tracking scores and showed significantly less prefrontal metabolism on a functional imaging paradigm. Taken together these findings are consistent with the hypothesis that PARS patients can be phenotyped by a specific pathophysiology.
ANALYSIS OF MUSCARINIC l PROMOTER POLYMORPHISMS ON RECEPTOR EXPRESSION AND OUTCOME TO ATYPICAL ANTIPSYCHOTIC TREATMENT D. T. Mancama,* I. Mata, J. Munro, S. Osborne, M. J. Arranz, R. K e r w i n
Psychological Medicine, Institute of Psychiatr); London, England, United Kingdom The muscarinic acetylcholine 1 (CHRM 1) receptor is ubiquitously expressed throughout the brain, with high densities found in those cortical and limbic regions thought to be important to the etiology of schizophrenia. Significant reductions in CHRM1 receptor density have been demonstrated in these regions amongst patients, and in this study we report comparable decreases in the levels of steady state frontal cortical CHRMI mRNA expressed in such individuals (F= 6.3, p=0.005). We have examined putative CHRM1 promoter sequences for genetic alterations that may be important to normal gene expression and, of those discovered, have identified significant association between a Tsp45I polymorphism and levels of receptor mRNA. Increased muscarinic activity has been proposed to exert a protective influence on the emergence of positive symptoms in schizophrenia, while a decrease in activity may impart an increase in positive symptoms. To investigate this potential, we have examined the CHRM 1 polymorphisms in olanzapine treated patients prospectively rated for response according to PANSS and GAF. We have also investigated the potential influence of these polymorphisms on outcome to clozapine treatment. No association however has been observed between genotype at the Tsp45I polymorphism and improvement in either positive or negative symptoms during treatment (significance p=0.75; p=0.58 respectively). Similarly no association has been found between the promoter polymorphisms and overall response to clozapine and olanzapine. Our results suggest that CHRM1 promoter polymorphisms do not appear to influence outcome to clozapine or olanzapine treatment, though they may be more relevant to the expression of this receptor in frontal cortical tissue.
GLUTAMATE RECEPTOR GENE (GRIN 1, GRIN2B) 1N SCHIZOPHRENIA: TDT AND CASECONTROLS ANALYSES L. Martucci,* A. C. Wong, J. Trakalo, T. Cate-Carter, E Ajmar, E. Di Maria, E Mandich, E Macciardi, J. L. Kennedy Neurogenetics, Centre for Addiction and Mental Health, Toronto, ON, Canada The etiology of schizophrenia remains unknown although many hypotheses have been formulated. For several years considerable interest has focused on the possible role of glutamate in schizophrenia: the N-Methyl-D-Aspartate Glutamate receptors (NMDAR) play critical roles in excitatory synaptic transmission, plasticity and excitotoxicity in the CNS, and act as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine and GABA. It has been suggested that a weakened glutamatergic tone increase the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. NMDAR functional properties are determined by subunit composition. NR1 is the only subunit that is expressed in all NMDA receptors. The NR2B subunit is equipped with an unusually long carboxyl-terminal domain that is believed to extend into the cytoplasm. Several lines of evidence suggest that this plays a crucial role in cellular signal transduetion. We focused on the study of two polymorphisms in the NR1 subunit gene (GRIND, and of one polymorphism on the NR2B subunit gene (GRIN2B): GRIN 1/1 is a C/G substitution localized on the 5' untranslated region (UTR); GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1, and GRIN2B is a T/G substitution located on the 3'UTR. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested for the presence of an association between GRIN1, GRIN2B and schizophrenia using a case-control and family-based association strategy. The results are as follows: for the case-control sample: GRIN1/I: chi-square=0.013, p=0.908; GRIN1/10: chi-square=0.544, p=0.461; GR1N2B: chi-square=2.795, p=0.095. For the nuclear families sample: GRINI/1, chi-square=2.19, p=0.14; GRIN1/10, chisquare=l.5, p=0.22. GRIN2B, chi-square=l.19, p=0.2753. Haplotype analyses showed a borderline significant result for the A/G haplotype (chi-square=3.86, p-value=0.049). An analysis of variance was conducted to test the association between specific genotype groups and age at onset. No significant results were observed: GRIN1/1, F[df=2]=0.42, p=0.659; GRIN1/10, F[df=2]=0.16, p=0.853; GRIN2B, F[d=2]=0.01, p=0.987. We are currently enlarging our samples to increase the power of the analyses.
PREMORBID A B N O R M A L I T I E S IN PSYCHOTIC PATIENTS ARE ASSOCIATED WITH SCHIZOTYPY IN THEIR RELATIVES I. Mata,* R C. S h a m , M. Beperet, J. A n ' o n d o , A. Albeniz, R. M. M u r r a y
Psychological Medicine, Institute of Psychiatry, London, United Kingdom Schizotypal personality disorder has come to be regarded as one phenotypic expression of familial-genetic liability to schizophrenia, although most studies have failed to confirm the specificity of schizotypy to categorically defined schizophrenia when relatives of patients with other psychoses are included. Some studies have adressed the issue of resemblance between psychotic symptoms of patients and
International Congress on Schizophrenia Research 2003