This project entitled "A Study on Risk Mutations of the Vulnerability Genes of Schizophrenia" (RIGOS) is a continuous effort following the well founded and arduous work of genetic study on schizophrenia (SCH) by the Genomic Psychiatry Study Group (GENOP) of National Taiwan University Hospital. So far the GENOP has established several important data banks, including DNA bank and lymphoblastoid (EVB transformed) cell bank of 725 affected sib-pair SCH families, 200 Trio SCH families, and 150 normal controls; and the clinical database of serial follow-ups. An ongoing project, Positional Cloning Study on the Vulnerability Genes of SCH (POCOS), carried out by the GENOP has found 11 candidate vulnerability genes with identified expression in the brain. Besides, on the basis of two related projects, the Multiple Psychopathological Study of SCH (MPSS) and the Etiological Study on SCH (SEFOS), the GENOP has established endophotype indicators for schizophrenia in neuropsychological and neurophysiological domains. The GENOP, a multidisciplinary research team, is thus ready to search for risk mutations of the candidate vulnerability genes for schizophrenia in this new proposal. The basic strategy of this RIGOS Project is to search for risk mutations, based on case-control design with sufficient statistical power, and then to validate these risk mutations by convergent evidence of genetic epidemiological analyses, functional variation studies using in vitro cell line experiments, microarray study, and neurophysiological study (PPI) on mice model. Thus, this RIGOS Project has integrated 5 lines of experimental designs to achieve 5 specific aims to identify and validate the risk mutations from 11 candidate vulnerability genes found in the ongoing POCOS project based on Taiwanese Sample. We are confident to be at the frontier work of searching for the risk mutations, with functional validity, of SCH. The achievement of the RIGOS will be a mile stone to create new era of genetic functional study to tackle pathophysiological mechanism of SCH and will be the basis of developing novel diagnostic method and novel intervention method at the early stage of SCH in the future.
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P50 event-related potential suppression (P50I) [Freedman et al., 1987; Olincy et al., 2000] and prepulse inhibition of the acoustic startle reflex (PPI) (Braff et al., 2001; Geyer et al., 2001) are reliable measurements. --- P50I ---
Both P50I and PPI mechanisms, under different neuronal circuits (Swerdlow et al., 2001; Adler et al., 1998), are out of subject's will control, and both are impaired in the patients of SCH (Freedman et al., 1987; Braff et al., 2001), in the spectrum disorder of schizotypal disorder (Cadenhead et al., 1998; Cadenhead et al., 2000) and clinically unaffected relatives of SCH patients (Siegel et al., 1984; Waldo et al., 1988; Waldo et al., 1991; Adler et al., 1992; Clementz et al., 1998; Cadenhead et al., 2000). --- P50I ---
Both deficits in P50I and PPI can be as the endophenotype indicators with different neural substrate processes. --- P50I ---
In this study, we intend to use P50I and PPI as specific endophenotype indicator for identifying the possible responsible risk mutations of the possible candidate vulnerability genes. --- P50I ---
This RIGOS project will take this endophenotype strategy for validation of risk mutations, especially by using attention impairment measured by CPT as well as P50I and PPI indicators. --- P50I ---