- Email: [email protected]
CTG trinucleotide repeats as an etiological factor in schizophrenia
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both in the IG and in the PG. We investigated anticipation, dividing the diagnoses into severity-category I (schizophrenia and schizoaffective disorder) and severity-category II (schizophreniform disorder, schizotypal and paranoid personality disorder) and examining the distribution of these categories between IG and PG . Analyzing AOO we tried to control for the cohort effect by selectingrandomly schizophrenic patients from a record of admissions in the University Hospital for Psychiatry in Vienna and matching patients ('cohort-sample') afterwards to both our IG and PG with regard to date of birth and sex. Patients from IG and PG and 'cohort-sample' originated from the same Austrian population and had an identical period of their lifetime being at risk to get into the sample. We found a significantdifferencebetween IG and PG regarding severity of illness (chi2=9.189, DF= I, p=0.002). AOO too differed between IG and PG (S=92.5000, Z=2.83533, p= 0.0046). As a control for a cohort-effect resulted no significant difference in AOO between the two generations of the 'cohortsample' (t= -1.63, df=68, 2-tailed p =0.108). Anticipation seems to be present in our families loaded with diseases out of the schizophrenia spectrum even after eliminating sampling biases like the cohort-effect.
Ilt , LARGE OR EXPANDED CAGjCfG TRINUCLEOTIDE REPEATS AS AN ETIOLOGICAL FACfOR IN SCHIZOPHRENIA John B. Vincent, H .Y. Meltzer, J.A. Lieberman, T. Breschel, M. McGinnis, A . Macedo, M.H. Azevedo, C.N. Pato, E .F. Torrey, I.I. Gottesman, A. Petronis and J.L. Kennedy
Clarke Institute ofPsychiatry. Neurogenetics Section. University of Toronto. 250 College Street, Toronto. ON. Canada. M5T 1R8 Many diseases that show ant icipation (increased severity/ decreased age of onset in successive generations) have recently been shown to have expanded trinucleotide repeats either within or adjacent to the disease causing gene. Evidenceof anticipation in schizophrenia has led us to search for large or expanded trinucleotide repeats that may be associated with a disease causing gene. Using the Repeat Expansion Detection (RED) technique, we have performed a matched pair analysis on 99 schizophrenia patients from North America and 99 controls matched for age sex and ethnicity. A second sample of 76 Portuguese schizophrenics and 46 controls was also analysed for evidence of CAG repeat expansion. No significant differences in CAG jcrG repeat sizes were observed for schizophrenia affecteds and matched controls, using a (crG)10 oligonucleotide. No evidence of intergenerational instability was observed amongst 14 schizophrenia triads. Furthermore, no significant sex effect was observed, and no significant differences in repeat size were found for responders and nonresponders to clozapine. There was no significant correlation (either positive or negative) between age of onset of disease and size of repeat. In a study of MZ twins discordant for schizophrenia the presence of larger RED product in the affected twin was not observed. The 7,6A CAG repeat on
18q21 also showed no differences between twins. We thus cannot conclude that CAG/crG trinucleotides are involved in psychotic disorders and that either the differences observed in other similar studies may be the result of population stratification (Sirugo et al., 1995) or that the increased occurrence of larger repeats amongst affected individuals is a much smaller effect than previously thought. However, the techniques used for detecting repeat expansions are of limited sensitivity. The involvement of other trinucleotide repeats or other expandable repeat sequences cannot be ruled out.
,So DETECfION, QUANTITATION AND ANALYSIS OF GENOMIC DIFFERENCES IN MONOZYGOTIC TWINS Cassandra L. Smith, Natalia E. Broude, Sergei A. Lukyanov, Joel H. Graber and Eugene D. Sverdlov
Centerfor AdvancedBiotechnology and Departmentsof Biomedical Engineering, Biologyand Pharmacology, Boston University. Boston. MA 02215and Shemyakin-Ovchinnikov Institutefor Bioorganic Chemistry. RussianAcademyof Sciences. Moscow, Russia Although the most similar human genomes are from monozygotic twins, many studies have found that monozygotic twins do not have identical genomes, Most studies of discordance in twins focus on individual genetic or phenotypic traits. We have developed a method which allows global genomic comparisons. This method divides the genome into subsets that are compared en masse. This method is being used to compare the genomes of monozygotic twin pairs that are concordant and discordant for schizophrenia or that are non-affected. The study focuses on genome subsets containing trinucleotide repeating sequences because an increase in number of such repeats are associated within an increasing number of neurodegenerative diseases. Quantitative analysis of the differences between co-twins revealed relative variations ranging from 0.13-0.17%. Interpair variation is much higher (0.5-2.6%) while experimental variation is about 0.12%. Ongoing experiments are focused on the determining the cause different levelsof intra-pair variation. Other experiments are focused on cloning and characterizing specific differences. Differences may be due to changes in targeted repeat length or nearby insertions, deletions or changes to restriction enzyme cleavage sites.
1"
ANALYSIS OF GENOMIC DNA FROM MONOZYGOTIC TWINS DISCORDANT FOR SCHIZOPHRENIA Yeping Sun, Jhy-Jhu Lin, Shuojia Li, Flora Leister Robert Yolken and The Stanley Neuropathology Consortium
Stanley Neurovirology Laboratory, Johns Hopkins University. Baltimore, MD 21287 It is postulated that interaction of genetic components and environmental factors play a role in the etiology of schizo-
both in the IG and in the PG. We investigated anticipation, dividing the diagnoses into severity-category I (schizophrenia and schizoaffective disorder) and severity-category II (schizophreniform disorder, schizotypal and paranoid personality disorder) and examining the distribution of these categories between IG and PG . Analyzing AOO we tried to control for the cohort effect by selectingrandomly schizophrenic patients from a record of admissions in the University Hospital for Psychiatry in Vienna and matching patients ('cohort-sample') afterwards to both our IG and PG with regard to date of birth and sex. Patients from IG and PG and 'cohort-sample' originated from the same Austrian population and had an identical period of their lifetime being at risk to get into the sample. We found a significantdifferencebetween IG and PG regarding severity of illness (chi2=9.189, DF= I, p=0.002). AOO too differed between IG and PG (S=92.5000, Z=2.83533, p= 0.0046). As a control for a cohort-effect resulted no significant difference in AOO between the two generations of the 'cohortsample' (t= -1.63, df=68, 2-tailed p =0.108). Anticipation seems to be present in our families loaded with diseases out of the schizophrenia spectrum even after eliminating sampling biases like the cohort-effect.
Ilt , LARGE OR EXPANDED CAGjCfG TRINUCLEOTIDE REPEATS AS AN ETIOLOGICAL FACfOR IN SCHIZOPHRENIA John B. Vincent, H .Y. Meltzer, J.A. Lieberman, T. Breschel, M. McGinnis, A . Macedo, M.H. Azevedo, C.N. Pato, E .F. Torrey, I.I. Gottesman, A. Petronis and J.L. Kennedy
Clarke Institute ofPsychiatry. Neurogenetics Section. University of Toronto. 250 College Street, Toronto. ON. Canada. M5T 1R8 Many diseases that show ant icipation (increased severity/ decreased age of onset in successive generations) have recently been shown to have expanded trinucleotide repeats either within or adjacent to the disease causing gene. Evidenceof anticipation in schizophrenia has led us to search for large or expanded trinucleotide repeats that may be associated with a disease causing gene. Using the Repeat Expansion Detection (RED) technique, we have performed a matched pair analysis on 99 schizophrenia patients from North America and 99 controls matched for age sex and ethnicity. A second sample of 76 Portuguese schizophrenics and 46 controls was also analysed for evidence of CAG repeat expansion. No significant differences in CAG jcrG repeat sizes were observed for schizophrenia affecteds and matched controls, using a (crG)10 oligonucleotide. No evidence of intergenerational instability was observed amongst 14 schizophrenia triads. Furthermore, no significant sex effect was observed, and no significant differences in repeat size were found for responders and nonresponders to clozapine. There was no significant correlation (either positive or negative) between age of onset of disease and size of repeat. In a study of MZ twins discordant for schizophrenia the presence of larger RED product in the affected twin was not observed. The 7,6A CAG repeat on
18q21 also showed no differences between twins. We thus cannot conclude that CAG/crG trinucleotides are involved in psychotic disorders and that either the differences observed in other similar studies may be the result of population stratification (Sirugo et al., 1995) or that the increased occurrence of larger repeats amongst affected individuals is a much smaller effect than previously thought. However, the techniques used for detecting repeat expansions are of limited sensitivity. The involvement of other trinucleotide repeats or other expandable repeat sequences cannot be ruled out.
,So DETECfION, QUANTITATION AND ANALYSIS OF GENOMIC DIFFERENCES IN MONOZYGOTIC TWINS Cassandra L. Smith, Natalia E. Broude, Sergei A. Lukyanov, Joel H. Graber and Eugene D. Sverdlov
Centerfor AdvancedBiotechnology and Departmentsof Biomedical Engineering, Biologyand Pharmacology, Boston University. Boston. MA 02215and Shemyakin-Ovchinnikov Institutefor Bioorganic Chemistry. RussianAcademyof Sciences. Moscow, Russia Although the most similar human genomes are from monozygotic twins, many studies have found that monozygotic twins do not have identical genomes, Most studies of discordance in twins focus on individual genetic or phenotypic traits. We have developed a method which allows global genomic comparisons. This method divides the genome into subsets that are compared en masse. This method is being used to compare the genomes of monozygotic twin pairs that are concordant and discordant for schizophrenia or that are non-affected. The study focuses on genome subsets containing trinucleotide repeating sequences because an increase in number of such repeats are associated within an increasing number of neurodegenerative diseases. Quantitative analysis of the differences between co-twins revealed relative variations ranging from 0.13-0.17%. Interpair variation is much higher (0.5-2.6%) while experimental variation is about 0.12%. Ongoing experiments are focused on the determining the cause different levelsof intra-pair variation. Other experiments are focused on cloning and characterizing specific differences. Differences may be due to changes in targeted repeat length or nearby insertions, deletions or changes to restriction enzyme cleavage sites.
1"
ANALYSIS OF GENOMIC DNA FROM MONOZYGOTIC TWINS DISCORDANT FOR SCHIZOPHRENIA Yeping Sun, Jhy-Jhu Lin, Shuojia Li, Flora Leister Robert Yolken and The Stanley Neuropathology Consortium
Stanley Neurovirology Laboratory, Johns Hopkins University. Baltimore, MD 21287 It is postulated that interaction of genetic components and environmental factors play a role in the etiology of schizo-