- Email: [email protected]
P3 amplitudes and latencies as vulnerability indicators
126
schizophrenia that involves: 1) examination of candidate genes at the nucleic acid level to identify sequence variants affecting protein structure or expression (i.e., changes that have a reasonable likelihood of being of functional significance); and 2) determination of disease association for a candidate gene by comparing the prevalence of sequence changes of likely functional significance in a large group of unrelated schizophrenic cases and ethnically-similar controls. We have screened or directly sequenced the D_, dopamine receptor (D,DR) gene in over 30 schizophrenics and only two silent mutations and one intronic mutation were found. Additional data have been generated on the D,, D,, and D, receptor genes and on exon 17 of the amyloid precursor protein. Our lab has developed PCR-based methodology to enhance the rate at which candidate genes may be examined for sequence changes (e.g., RNA-based single strand conformational polymorphism gels; dideoxy fingerprinting). A DNA bank on approximately 420 DSM-III-R defined schizophrenics and 1000 ethnically-similar controls has been established. In addition, we have developed statistical methodology for the estimation of required sample sizes and for the evaluation of statistical power using both unrelated controls and parent controls.
P3 AMPLITUDES VULNERABILITY
AND LATENCIES INDICATORS
AS
E. Squires-Wheeler*,
D. Friedman, L. Erlenmeyer-Kimling
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Interest in applying endogenous electrophysiological measures as indicators of vulnerability to expression of psychotic disorders has increased (Blackwood et. al. 1991a,b; Cloninger 1990; Nuechterlein 1990). We have recently evaluated vulnerability indicator properties such as sensitivity and specificity for one vulnerability indicator (i.e. endophenotypic) candidate, P3 amplitude decrements (Friedman and Squires-Wheeler, in press). The expectation of a specific link between decreased P3 amplitudes recorded in adolescence and subsequent schizophrenic spectrum clinical status in young adulthood in subjects with psychiatrically ill parents (117 offspring from the New York High Risk Study) was not observed. However a significant relationship was seen for reduced amplitudes and a measure of global personality functioning. We present here extended work to discern a more precise clinical profile underlying the reduced amplitude-global personality functioning association. First we report results of analyses undertaken to replicate Ward’s (1991) finding of a relationship between negative symptoms and P3 amplitude reductions. The correlations of P3 amplitude with several constructions of negative symptoms (using both self report and interviewer observations) fell short of statistical significance for all parental diagnostic groups (schizophrenic disorder, affective disorder and normal control parents). Second, we report results from explicitly exploratory analyses using discriminant function and canonical correlation approaches to resolve the pattern of psychopathology maximally associated with P3 parameters including
amplitude and latency. The utility of this approach lies in the hope that a more robust association between putative endophenotypes and clinical features will yield endophenotype candidates with higher sensitivities and specificities.
NEUROPSYCHOLOGICAL FUNCTIONING, NEGATIVE SYMPTOMS AND THE SCHIZOPHRENIA GENOTYPE M.T. Tsuang*, S.V. Faraone, J.R. Pepple, M.J. Lyons, W.S. Kremen. L.J. Seidman BrocktonlW. Roxbury VAMC, Psychiatry Svc, 116A. 940 Belmont St., Brockton, MA 02401, USA Neuropsychological impairment and negative symptoms aggregate among the biological relatives of schizophrenic patients, suggesting that they may reflect the genetic etiology of the illness. We examined these traits in schizophrenic patients, their first degree biological relatives and a control sample. Andreasen’s Scale for the Assessment of Negative Symptoms (SANS) assessed psychopathological aspects of the deficit syndrome and a comprehensive neuropsychological battery assessed cognitive functioning. The neuropsychological battery used tests sensitive to dysfunctions mediated by brain areas believed to be impaired in schizophrenia. Diagnoses of patients and relatives used direct psychiatric interviews and reviews of medical records. We previously suggested that both negative symptoms and neuropsychological functioning may be manifestations of the genetic predisposition to schizophrenia. We now present data to test this hypothesis and clarify the interrelationships among these indicators. Our data show that the cognitive impairment of relatives is similar (but milder) to deficits observed in schizophrenic patients. These indicate subtle prefrontal temporal-limbic and attentional dysfunction. We discuss the ability of these measures to classify relatives with the schizophrenia genotype along with their relationship to negative symptoms and other psychiatric manifestations of the genotype.
GENETIC
MAPPING
ON CHROMOSOME
22
Homer0 Vallada*, Michael Gill, Shin Nanko, Michael Owen, Robin Murray, David Collier Genetics Section, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK A large body of work comparing the incidence of schizophrenia in twin and adoption studies, dating back more than fifty years, supports a strong genetic component for the disease. Although the mode of transmission is unknown, it is unlikely that a single major locus can account for the transmission of schizophrenia as a whole. It seems also unlikely to be a heterogeneous mixture of single gene disorders alone. As seen with
schizophrenia that involves: 1) examination of candidate genes at the nucleic acid level to identify sequence variants affecting protein structure or expression (i.e., changes that have a reasonable likelihood of being of functional significance); and 2) determination of disease association for a candidate gene by comparing the prevalence of sequence changes of likely functional significance in a large group of unrelated schizophrenic cases and ethnically-similar controls. We have screened or directly sequenced the D_, dopamine receptor (D,DR) gene in over 30 schizophrenics and only two silent mutations and one intronic mutation were found. Additional data have been generated on the D,, D,, and D, receptor genes and on exon 17 of the amyloid precursor protein. Our lab has developed PCR-based methodology to enhance the rate at which candidate genes may be examined for sequence changes (e.g., RNA-based single strand conformational polymorphism gels; dideoxy fingerprinting). A DNA bank on approximately 420 DSM-III-R defined schizophrenics and 1000 ethnically-similar controls has been established. In addition, we have developed statistical methodology for the estimation of required sample sizes and for the evaluation of statistical power using both unrelated controls and parent controls.
P3 AMPLITUDES VULNERABILITY
AND LATENCIES INDICATORS
AS
E. Squires-Wheeler*,
D. Friedman, L. Erlenmeyer-Kimling
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Interest in applying endogenous electrophysiological measures as indicators of vulnerability to expression of psychotic disorders has increased (Blackwood et. al. 1991a,b; Cloninger 1990; Nuechterlein 1990). We have recently evaluated vulnerability indicator properties such as sensitivity and specificity for one vulnerability indicator (i.e. endophenotypic) candidate, P3 amplitude decrements (Friedman and Squires-Wheeler, in press). The expectation of a specific link between decreased P3 amplitudes recorded in adolescence and subsequent schizophrenic spectrum clinical status in young adulthood in subjects with psychiatrically ill parents (117 offspring from the New York High Risk Study) was not observed. However a significant relationship was seen for reduced amplitudes and a measure of global personality functioning. We present here extended work to discern a more precise clinical profile underlying the reduced amplitude-global personality functioning association. First we report results of analyses undertaken to replicate Ward’s (1991) finding of a relationship between negative symptoms and P3 amplitude reductions. The correlations of P3 amplitude with several constructions of negative symptoms (using both self report and interviewer observations) fell short of statistical significance for all parental diagnostic groups (schizophrenic disorder, affective disorder and normal control parents). Second, we report results from explicitly exploratory analyses using discriminant function and canonical correlation approaches to resolve the pattern of psychopathology maximally associated with P3 parameters including
amplitude and latency. The utility of this approach lies in the hope that a more robust association between putative endophenotypes and clinical features will yield endophenotype candidates with higher sensitivities and specificities.
NEUROPSYCHOLOGICAL FUNCTIONING, NEGATIVE SYMPTOMS AND THE SCHIZOPHRENIA GENOTYPE M.T. Tsuang*, S.V. Faraone, J.R. Pepple, M.J. Lyons, W.S. Kremen. L.J. Seidman BrocktonlW. Roxbury VAMC, Psychiatry Svc, 116A. 940 Belmont St., Brockton, MA 02401, USA Neuropsychological impairment and negative symptoms aggregate among the biological relatives of schizophrenic patients, suggesting that they may reflect the genetic etiology of the illness. We examined these traits in schizophrenic patients, their first degree biological relatives and a control sample. Andreasen’s Scale for the Assessment of Negative Symptoms (SANS) assessed psychopathological aspects of the deficit syndrome and a comprehensive neuropsychological battery assessed cognitive functioning. The neuropsychological battery used tests sensitive to dysfunctions mediated by brain areas believed to be impaired in schizophrenia. Diagnoses of patients and relatives used direct psychiatric interviews and reviews of medical records. We previously suggested that both negative symptoms and neuropsychological functioning may be manifestations of the genetic predisposition to schizophrenia. We now present data to test this hypothesis and clarify the interrelationships among these indicators. Our data show that the cognitive impairment of relatives is similar (but milder) to deficits observed in schizophrenic patients. These indicate subtle prefrontal temporal-limbic and attentional dysfunction. We discuss the ability of these measures to classify relatives with the schizophrenia genotype along with their relationship to negative symptoms and other psychiatric manifestations of the genotype.
GENETIC
MAPPING
ON CHROMOSOME
22
Homer0 Vallada*, Michael Gill, Shin Nanko, Michael Owen, Robin Murray, David Collier Genetics Section, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK A large body of work comparing the incidence of schizophrenia in twin and adoption studies, dating back more than fifty years, supports a strong genetic component for the disease. Although the mode of transmission is unknown, it is unlikely that a single major locus can account for the transmission of schizophrenia as a whole. It seems also unlikely to be a heterogeneous mixture of single gene disorders alone. As seen with