Ignite Creation Date:
2024-05-05 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00155207
Status:
UNKNOWN
Last Update Posted:
2005-11-28
First Post:
2005-09-09
Brief Title:
A Study on Risk Mutations of Vulnerability Genes of Schizophrenia
Sponsor:
National Taiwan University Hospital
Organization:
National Taiwan University Hospital
Study Overview
Official Title:
A Study on Risk Mutations of Vulnerability Genes of Schizophrenia
Status:
UNKNOWN
Status Verified Date:
2005-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
Detailed Description:
4a Specific Aims In our previous work based on a Taiwanese sample we have found that schizophrenia was significantly associated with 11 candidate genes including GNPAT 1q421 DISC1 1q421 MRDS1 6p243 NOTCH4 6p213 NRG1 8p21-p12 DAAO 12q22 G72 13q32 CHRNA7 15q14 PRODH 22q1121 HMOXI 22q12 and CACNG2 22q12 In this 3-year proposal we have 5 specific aims in which aim 1 is a continuation of our previous study of the Positional Cloning Study of SCH POCOS using family data while aims 2 to 5 are newly developed research goals
Specific Aim 1 To investigate tighter association of these 11 candidate vulnerability genes with different subtypes defined by clinical or endophenotype variables The endophenotype variables include the neuropsychological functions of sustained attention measured by continuous performance test CPT executive function measured by Wisconsin Card Sorting Test WSCT and the skin physiological function of niacin flushing responses
The hypothesis to be tested is that schizophrenia is genetically heterogeneous and the specific risk SNP markers or specific risk SNPs haplotypes of different candidate genes will be associated with specific clinical subtype or specific endophenotype indicators with higher degree of statistical significance
Specific Aim 2 To search for functional risk mutations of these candidate genes using direct sequencing technique and to investigate the contributing genetic variance of the specific risk mutations in specific subtypes of schizophrenia as mentioned in specific Aim 1 using case-control study design The interaction effects of these functional risk mutations will be explored
The hypothesis to be tested is that there are several specific risk mutations from 11 candidate genes The contributing variances of these different risk mutations will be different
Specific Aim 3 To find the variation of functional expressions of these identified risk mutations in Epstein-Barr virus EBV transformed lymphoblastoid cell lines of the patient subjects and neuronal cell-lines
We hypothesize that these candidate genes have expression discriminations when carrying risk mutations which will be able to be detected from EBV-transformed lymphoblastoid cells of these patients and neuronal cell-lines or from constructed reporter gene expression
Specific Aim 4 To explore and clarify the candidate genes responsible for the impaired niacin skin flushing response in schizophrenia
We hypothesized that difference in the skin niacin flushing response will reveals difference in the gene expression in the lymphocytes using microarray approach based on a matched case- control design
Specific Aim 5 To establish a procedure to assess the prepulse inhibition function PPI in normal mice as the endophenotype indicator of schizophrenia and test its validity with acute or chronic administration of amphetamine This animal model will serve further functional study on the knock-out or knock-down mice carrying these identified risk mutations
The hypothesis to be tested is that acute or chronic administration of amphetamine will block PPI in wild-type mice
In addition we will explore during the conducting of this proposal the following feasibilities 1 To obtain human brain tissues for studying the functional expressions of these vulnerability genes with specific risk mutations 2 To employ the animal model to assess neurophysiological and behavioral abnormalities in mice carrying the functional risk mutations 3 To explore novel treatment for preventing the abnormal neurobiological process due to the risk mutations and 4To develop early detection and early intervention program including genetic counseling based on the data of risk mutations
4 Research Plan continuation 4b Background and Significance Schizophrenia SCH is a devastating and stigmatized psychiatric disorder with high genetic loading The identification of vulnerability genes of SCH is at dawn nowadays As the vulnerability genes and the specific risk mutations are identified there will come the revolutionary development in SCH research and clinical practice including reliable and valid diagnosis based on genetic and related neurobiological data novel treatment and early prevention of schizophrenia based on the knowledge of abnormal gene function and its interaction with the environmental factors
The Genomic Psychiatry Study Group GENOP a multidisciplinary team of National Taiwan University Hospital has been successfully operating in studying genetic factors in the psychopathology of SCH This GENOP has carried out the positional cloning study on vulnerability genes of Schizophrenia POCOS supported by NRPGM in these 3 years and has found 11 candidates vulnerability genes through dense SNP fine mapping study This GENOP also have a thorough neurobiological and clinical psychopathological study Hwu et al 2002 Chen et al 1998 Chiu et al 2004 Hsieh et al 2004 Hwu 1999 Hwu et al 2003 Thus the GENOP is ready to take a step further to search for risk mutations of SCH as proposed here
We conclude that the finding of vulnerability genes for schizophrenia is at dawn based on the following lines of empirical evidence
1 Genetic Epidemiological Study SCH is a highly heritable disease based on family twin Kendler KS 1983 Gottesman II 1993 Prescott and Gottesman II 1993 and adoption Heston 1966 Kety et al 1968 1994 Kendler et al 1994 studies with an heritability of 070 Tsuang et al 1980 1995 Guze et al 1983 Kendler 1988 and a λ risk to first-degree relatives versus controls value of 10 Kendler KS 1983 Gottesman II 1993 Prescott and Gottesman II 1993 Chang et al 2002 An oligogenetic model of SCH etiology was commonly accepted Faraone and Tsuang 1985 Risch and Baron 1984 Vogler et al 1990 Risch 1990
2 Molecular Genetic Studies of Schizophrenia 2-1 Linkage Analyses Genome-wide scans of SCH for the decade found that many chromosome regions had suggestive evidence for linkage Coon et al 1994 Shaw et al 1998 Levinson et al1998 Blouin et al 1998 Kaufmann et al1998 Faraone et al 1998 Rees et al 1999 Williams et al 1999 Hovatta et al 1999 Brzustowicz et al 2000 whereas subsequent studies revealed a replication and non-replication pattern Riley 2000 Inadequate sample size and mixed ethnicity might be the major methodological problems Altmuller et al 2001 Hauser et al 1996
2-2 Candidate chromosome region approach A balance translocation 1 11 q421 q143 was found to be associated with major mental illness including schizophrenia St Clair et al 1990 The novel gene DISC1 at chromosome 1q421 was repeatedly found to have significant association with SCH including our Taiwanese samples Millar et al 2000 2001 Hovatta et al 1999 Ekelund et al 2001 Hwu et al 2001 Ekelund et al 2004 Liu YL et al 2004
2-3 Candidate gene approach Many candidate genes such as dopamine D1 D2 D3 D4 and D5 serotonin and glutamate receptor genes based on psychopharmacological hypothesis Asherson et al 1995 Breyler et al 1995 Hranilovic et al 2000 Catalano et al 1993 Serretti et al 1999 Chen et al 1996 1997 as well as developmental- and physiological-based genes such as neuron growth related genes Margolis et al 1994 phospholipase genes Peet 1998 Wei 1998 and a potassium channel gene hKCa3KCNN3 Dror et al 1999 have been reported to have association though not consistently with schizophrenia The mixture of ethnicity in the sample may inflate the type I errors
2-4 Association study using SNP fine mapping and family internal control method By genetic epidemiological guideline such as using linkage disequilibrium strategy and parent-offspring trios as internal control to guide the improved method to locate the susceptibility genes of complex disorder Risch and Merikangas 1996 Owen et al 2000 Baron 2001 there were about 10 candidate genes found by using this modality of study approach Elkin et al 2004 These candidate genes included RGS4 1q Mirnics et al 2001 MRDS1 6p243 DTNBP1 6p223 Straub et al 2002 Tang et al 2003 van Den Bogaert et al 2003 van den Oord et al 2003 TNFa 6p22 Boin et al 2001 Pae et al 2003 NOTCH4 6p213 Wei and Hemmings 2000 Fan et al 2002 Sklar et al 2001 Skol et al 2003 Takahashi et al 2003 PPP3CC 8p213 Gerber et al 2003 NRG18p21-p12 Stefansson et al 2002 2003Yang et al 2003 DAAO12q22 Chumakov et al 2002 G7213q33 Chumakov et al 2002 CHRNA715q14 Leonard S et al 2002 PRODH22q1121 Liu et al 2002 Jacquet et al 2002 COMT22q1121 Shifman et al 2002 Nevertheless all these candidate genes still wait to be replicated in different study samples
The GENOP of NTUH by using dense SNP fine mapping method have found that 8 significant candidate genes of MRDS16p243 NOTCH46p213 NRG18p21-p12 DAAO12q22 G7213q32 and PRODH22q1121 HMOXI 22q12 and CACNG2 22q12 Liu et al 2004 This research team is thus ready to take a step further to search for the risk mutations of these candidate genes and the validation study of these risk mutations Based on the meta-analysis of published studies Altmuller et al 2001 and Risch et al2000 suggested that high density SNP association analysis in combination with functional genomic data may be necessary to detect susceptibility loci which may be of small effect for complex human disease as shown in a few recent reports Emamian et al 2004 Mukai et al 2004 This proposed RIGOS will follow this strategy as the main approach as shown in our specific aims
3 Endophenotype indictors and Issue of Heterogeneity of SCH 3-1 Neurobiological Impairment in Schizophrenia SCH was found to have impairment in neuropsychological functions of executive function sustained attention measured and working memory Goldberg et al 1993 with underlied frontostriatal dysfunction Elliot et al 1995 or dysfunction of frontal-temporal-limbic circuit Gold and Harvey 1993 or dorsolateral prefrontal cortex Weinberger et al 1988 Berman et al 1988
These impaired neurobiological functions had significant association with specific clinical symptoms Nuechterlein et al 1986 Hain et al 1993 Johnstone and Frith 1996 Liu et al 1997 Nuechterlein et al 1986 Strauss et al 1993 Nelson et al 1998 Liu et al 1997 and enduring long term disability Weinberger et al 1986 Goldberg et al 1988
SCH is characterized by core-deficits in information processing and attentional mechanism Bleuler 1911 Kraepelin and Robertson 1919 McGhie and Chapman 1961 Venables 1964 Braff and Geyer 1990 which was due to the impairment of filtering or gating function of brain Braff and Geyer 1990 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 Both P50I and PPI mechanisms under different neuronal circuits Swerdlow et al 2001 Adler et al 1998 are out of subjects 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 Both deficits in P50I and PPI can be as the endophenotype indicators with different neural substrate processes 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
Animal studies have shown that the PPI deficits could be induced pharmacologically by agents altering systems implicated in the neurobiology of schizophrenia such as dopaminergic or NMDA glutamatergic neurotransmission Mansbach et al 1988 Hutchison Swift 1999 This experimentally induced PPI impairment by amphetamine has been conceived as a putative animal model with face predictive and construct validities for certain schizophrenic symptoms Koch 1999 Swerdlow et al 2000
Impairment of Niacin Skin Flush Response in Schizophrenia The niacin induced vasodilatory response was either absent or impaired in schizophrenic patients Horrobin 1980 Wilson and Douglass 1986 Fielder et al 1986 Hudson et al 1997 Rybakowski and Weterle 1991 Hudson et al 1997 1999 Ward et al 1998 Puri et al 2001 Shah et al 2000 Maclean et al 2003 There is no significant relationship between antipsychotic drug dose and niacin sensitivity Hundson et al 1997 Messamore et al 2003
The niacin sensitivity may be through the nicotinic acid receptor HM74 low affinity receptor and HM74a high affinity receptor recently identified Wise et al 2003 Soga et al 2003 and they are both Gi-G-protein-coupled receptors GPCR The two receptors were expressed in the lymphocytes Wise et al 2003 The detail molecules and signaling pathway involved in niacin skin flush response still remained to be clarified In this RIGOS project it is desirable to explore the possible responsible genes in this un-studied area using microarray method
3-2 Endophenotype Approach in Molecular Genetic Studies of Schizophrenia To face the genetic heterogeneity of SCH an alternative strategy was to use specific neurobiological characteristic of the illness as an endophenotype reflecting the effect of a single genetic alteration Lander 1988 In this respect deficits on the Continuous Performance Test CPT have been postulated to be a potential endophenotype of the genetic susceptibility to SCH Chen and Faraone 2000 Grove et al 1991 Mirsky et al 1995 Chen et al 1998
CPT deficit was a potential endophenotype of the genetic susceptibility to SCH Chen and Faraone 2000 Grove et al 1991 Mirsky et al 1995 Chen et al 1998
This endophenotype strategy has been successful in mapping of a neurophysiological deficit decrease of P50 inhibition to loci at chromosome 15q13-14 Freedman et al 1997 The other neurobiological deficit eye-tracking dysfunction of schizophrenia has been mapped to chromosome 6p23-21 with the maximum multipoint lod score of 402 Arolt et al 1996 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
3-3 Issue of Heterogeneity Genetic and clinical heterogeneity is the main issue in this area of study Searching for valid clinical subtype and endophenotype are critical for a breaking through study Our GENOP group had substantial psychopathological data in this area and the RIGOS project will take this strategy
4 Functions of Candidate Vulnerability Genes This RIGOS project will tackle on these 11 candidates vulnerability genes identified by our previous POCOS project The neuronal functions of these 11 candidate genes to be studied have not been well characterized Current knowledge on the functions of some of these 11 candidate genes are listed as the following the GNPAT is a dihydroxyacetonephosphateacyltransferase DHAPAT or DAPAT participating in the etherphospholipid biosynthesis Ofman et al 2001 the NOTCH4 is a heterodimer receptor involving in the vascular and articular cartilage development Hayes et al 2003 Iso et al 2003 the NRG1 neuregulin 1 is a group of isoform proteins produced from NRG1 gene by alternative splicing these isomers interact with ERBB receptor and induce the growth and differentiation of neuronal and glial cells Kerber et al 2003 Fallon et al 2004 The DAAO D-amino-acid oxidase is a peroxisomal enzyme activated by G72 D-amino acid oxidase activator Chumakov et al 2002 The CHRNA7 is a nicotinic acetylcholine receptor subunit belonging to the superfamily of ligand-gated ion channels and involving in the development of the central nervous system Agulhon et al 1999 Raux et al 2002 The PRODH proline dehydrogenase is an enzyme catalyzing proline to Δ-1-pyrroline-5-carboxylate P5C the first step in the conversion of proline to glutamate Harrison and Owen 2003 Lee et al 2003 Deletion of this gene has been associated with hyperprolinemia Jacquet et al 2002 The functional roles of these genes on the neuronal cells warrant further investigation to predict the possible pathological process for schizophrenia In this RIGOS project well use in vitro cell-line to do functional laboratory study to validate any of these risk mutations identified in this RIGOS project
Specific Aim 1 To investigate tighter association of these 11 candidate vulnerability genes with different subtypes defined by clinical or endophenotype variables The endophenotype variables include the neuropsychological functions of sustained attention measured by continuous performance test CPT executive function measured by Wisconsin Card Sorting Test WSCT and the skin physiological function of niacin flushing responses
The hypothesis to be tested is that schizophrenia is genetically heterogeneous and the specific risk SNP markers or specific risk SNPs haplotypes of different candidate genes will be associated with specific clinical subtype or specific endophenotype indicators with higher degree of statistical significance
Specific Aim 2 To search for functional risk mutations of these candidate genes using direct sequencing technique and to investigate the contributing genetic variance of the specific risk mutations in specific subtypes of schizophrenia as mentioned in specific Aim 1 using case-control study design The interaction effects of these functional risk mutations will be explored
The hypothesis to be tested is that there are several specific risk mutations from 11 candidate genes The contributing variances of these different risk mutations will be different
Specific Aim 3 To find the variation of functional expressions of these identified risk mutations in Epstein-Barr virus EBV transformed lymphoblastoid cell lines of the patient subjects and neuronal cell-lines
We hypothesize that these candidate genes have expression discriminations when carrying risk mutations which will be able to be detected from EBV-transformed lymphoblastoid cells of these patients and neuronal cell-lines or from constructed reporter gene expression
Specific Aim 4 To explore and clarify the candidate genes responsible for the impaired niacin skin flushing response in schizophrenia
We hypothesized that difference in the skin niacin flushing response will reveals difference in the gene expression in the lymphocytes using microarray approach based on a matched case- control design
Specific Aim 5 To establish a procedure to assess the prepulse inhibition function PPI in normal mice as the endophenotype indicator of schizophrenia and test its validity with acute or chronic administration of amphetamine This animal model will serve further functional study on the knock-out or knock-down mice carrying these identified risk mutations
The hypothesis to be tested is that acute or chronic administration of amphetamine will block PPI in wild-type mice
In addition we will explore during the conducting of this proposal the following feasibilities 1 To obtain human brain tissues for studying the functional expressions of these vulnerability genes with specific risk mutations 2 To employ the animal model to assess neurophysiological and behavioral abnormalities in mice carrying the functional risk mutations 3 To explore novel treatment for preventing the abnormal neurobiological process due to the risk mutations and 4To develop early detection and early intervention program including genetic counseling based on the data of risk mutations
4 Research Plan continuation 4b Background and Significance Schizophrenia SCH is a devastating and stigmatized psychiatric disorder with high genetic loading The identification of vulnerability genes of SCH is at dawn nowadays As the vulnerability genes and the specific risk mutations are identified there will come the revolutionary development in SCH research and clinical practice including reliable and valid diagnosis based on genetic and related neurobiological data novel treatment and early prevention of schizophrenia based on the knowledge of abnormal gene function and its interaction with the environmental factors
The Genomic Psychiatry Study Group GENOP a multidisciplinary team of National Taiwan University Hospital has been successfully operating in studying genetic factors in the psychopathology of SCH This GENOP has carried out the positional cloning study on vulnerability genes of Schizophrenia POCOS supported by NRPGM in these 3 years and has found 11 candidates vulnerability genes through dense SNP fine mapping study This GENOP also have a thorough neurobiological and clinical psychopathological study Hwu et al 2002 Chen et al 1998 Chiu et al 2004 Hsieh et al 2004 Hwu 1999 Hwu et al 2003 Thus the GENOP is ready to take a step further to search for risk mutations of SCH as proposed here
We conclude that the finding of vulnerability genes for schizophrenia is at dawn based on the following lines of empirical evidence
1 Genetic Epidemiological Study SCH is a highly heritable disease based on family twin Kendler KS 1983 Gottesman II 1993 Prescott and Gottesman II 1993 and adoption Heston 1966 Kety et al 1968 1994 Kendler et al 1994 studies with an heritability of 070 Tsuang et al 1980 1995 Guze et al 1983 Kendler 1988 and a λ risk to first-degree relatives versus controls value of 10 Kendler KS 1983 Gottesman II 1993 Prescott and Gottesman II 1993 Chang et al 2002 An oligogenetic model of SCH etiology was commonly accepted Faraone and Tsuang 1985 Risch and Baron 1984 Vogler et al 1990 Risch 1990
2 Molecular Genetic Studies of Schizophrenia 2-1 Linkage Analyses Genome-wide scans of SCH for the decade found that many chromosome regions had suggestive evidence for linkage Coon et al 1994 Shaw et al 1998 Levinson et al1998 Blouin et al 1998 Kaufmann et al1998 Faraone et al 1998 Rees et al 1999 Williams et al 1999 Hovatta et al 1999 Brzustowicz et al 2000 whereas subsequent studies revealed a replication and non-replication pattern Riley 2000 Inadequate sample size and mixed ethnicity might be the major methodological problems Altmuller et al 2001 Hauser et al 1996
2-2 Candidate chromosome region approach A balance translocation 1 11 q421 q143 was found to be associated with major mental illness including schizophrenia St Clair et al 1990 The novel gene DISC1 at chromosome 1q421 was repeatedly found to have significant association with SCH including our Taiwanese samples Millar et al 2000 2001 Hovatta et al 1999 Ekelund et al 2001 Hwu et al 2001 Ekelund et al 2004 Liu YL et al 2004
2-3 Candidate gene approach Many candidate genes such as dopamine D1 D2 D3 D4 and D5 serotonin and glutamate receptor genes based on psychopharmacological hypothesis Asherson et al 1995 Breyler et al 1995 Hranilovic et al 2000 Catalano et al 1993 Serretti et al 1999 Chen et al 1996 1997 as well as developmental- and physiological-based genes such as neuron growth related genes Margolis et al 1994 phospholipase genes Peet 1998 Wei 1998 and a potassium channel gene hKCa3KCNN3 Dror et al 1999 have been reported to have association though not consistently with schizophrenia The mixture of ethnicity in the sample may inflate the type I errors
2-4 Association study using SNP fine mapping and family internal control method By genetic epidemiological guideline such as using linkage disequilibrium strategy and parent-offspring trios as internal control to guide the improved method to locate the susceptibility genes of complex disorder Risch and Merikangas 1996 Owen et al 2000 Baron 2001 there were about 10 candidate genes found by using this modality of study approach Elkin et al 2004 These candidate genes included RGS4 1q Mirnics et al 2001 MRDS1 6p243 DTNBP1 6p223 Straub et al 2002 Tang et al 2003 van Den Bogaert et al 2003 van den Oord et al 2003 TNFa 6p22 Boin et al 2001 Pae et al 2003 NOTCH4 6p213 Wei and Hemmings 2000 Fan et al 2002 Sklar et al 2001 Skol et al 2003 Takahashi et al 2003 PPP3CC 8p213 Gerber et al 2003 NRG18p21-p12 Stefansson et al 2002 2003Yang et al 2003 DAAO12q22 Chumakov et al 2002 G7213q33 Chumakov et al 2002 CHRNA715q14 Leonard S et al 2002 PRODH22q1121 Liu et al 2002 Jacquet et al 2002 COMT22q1121 Shifman et al 2002 Nevertheless all these candidate genes still wait to be replicated in different study samples
The GENOP of NTUH by using dense SNP fine mapping method have found that 8 significant candidate genes of MRDS16p243 NOTCH46p213 NRG18p21-p12 DAAO12q22 G7213q32 and PRODH22q1121 HMOXI 22q12 and CACNG2 22q12 Liu et al 2004 This research team is thus ready to take a step further to search for the risk mutations of these candidate genes and the validation study of these risk mutations Based on the meta-analysis of published studies Altmuller et al 2001 and Risch et al2000 suggested that high density SNP association analysis in combination with functional genomic data may be necessary to detect susceptibility loci which may be of small effect for complex human disease as shown in a few recent reports Emamian et al 2004 Mukai et al 2004 This proposed RIGOS will follow this strategy as the main approach as shown in our specific aims
3 Endophenotype indictors and Issue of Heterogeneity of SCH 3-1 Neurobiological Impairment in Schizophrenia SCH was found to have impairment in neuropsychological functions of executive function sustained attention measured and working memory Goldberg et al 1993 with underlied frontostriatal dysfunction Elliot et al 1995 or dysfunction of frontal-temporal-limbic circuit Gold and Harvey 1993 or dorsolateral prefrontal cortex Weinberger et al 1988 Berman et al 1988
These impaired neurobiological functions had significant association with specific clinical symptoms Nuechterlein et al 1986 Hain et al 1993 Johnstone and Frith 1996 Liu et al 1997 Nuechterlein et al 1986 Strauss et al 1993 Nelson et al 1998 Liu et al 1997 and enduring long term disability Weinberger et al 1986 Goldberg et al 1988
SCH is characterized by core-deficits in information processing and attentional mechanism Bleuler 1911 Kraepelin and Robertson 1919 McGhie and Chapman 1961 Venables 1964 Braff and Geyer 1990 which was due to the impairment of filtering or gating function of brain Braff and Geyer 1990 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 Both P50I and PPI mechanisms under different neuronal circuits Swerdlow et al 2001 Adler et al 1998 are out of subjects 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 Both deficits in P50I and PPI can be as the endophenotype indicators with different neural substrate processes 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
Animal studies have shown that the PPI deficits could be induced pharmacologically by agents altering systems implicated in the neurobiology of schizophrenia such as dopaminergic or NMDA glutamatergic neurotransmission Mansbach et al 1988 Hutchison Swift 1999 This experimentally induced PPI impairment by amphetamine has been conceived as a putative animal model with face predictive and construct validities for certain schizophrenic symptoms Koch 1999 Swerdlow et al 2000
Impairment of Niacin Skin Flush Response in Schizophrenia The niacin induced vasodilatory response was either absent or impaired in schizophrenic patients Horrobin 1980 Wilson and Douglass 1986 Fielder et al 1986 Hudson et al 1997 Rybakowski and Weterle 1991 Hudson et al 1997 1999 Ward et al 1998 Puri et al 2001 Shah et al 2000 Maclean et al 2003 There is no significant relationship between antipsychotic drug dose and niacin sensitivity Hundson et al 1997 Messamore et al 2003
The niacin sensitivity may be through the nicotinic acid receptor HM74 low affinity receptor and HM74a high affinity receptor recently identified Wise et al 2003 Soga et al 2003 and they are both Gi-G-protein-coupled receptors GPCR The two receptors were expressed in the lymphocytes Wise et al 2003 The detail molecules and signaling pathway involved in niacin skin flush response still remained to be clarified In this RIGOS project it is desirable to explore the possible responsible genes in this un-studied area using microarray method
3-2 Endophenotype Approach in Molecular Genetic Studies of Schizophrenia To face the genetic heterogeneity of SCH an alternative strategy was to use specific neurobiological characteristic of the illness as an endophenotype reflecting the effect of a single genetic alteration Lander 1988 In this respect deficits on the Continuous Performance Test CPT have been postulated to be a potential endophenotype of the genetic susceptibility to SCH Chen and Faraone 2000 Grove et al 1991 Mirsky et al 1995 Chen et al 1998
CPT deficit was a potential endophenotype of the genetic susceptibility to SCH Chen and Faraone 2000 Grove et al 1991 Mirsky et al 1995 Chen et al 1998
This endophenotype strategy has been successful in mapping of a neurophysiological deficit decrease of P50 inhibition to loci at chromosome 15q13-14 Freedman et al 1997 The other neurobiological deficit eye-tracking dysfunction of schizophrenia has been mapped to chromosome 6p23-21 with the maximum multipoint lod score of 402 Arolt et al 1996 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
3-3 Issue of Heterogeneity Genetic and clinical heterogeneity is the main issue in this area of study Searching for valid clinical subtype and endophenotype are critical for a breaking through study Our GENOP group had substantial psychopathological data in this area and the RIGOS project will take this strategy
4 Functions of Candidate Vulnerability Genes This RIGOS project will tackle on these 11 candidates vulnerability genes identified by our previous POCOS project The neuronal functions of these 11 candidate genes to be studied have not been well characterized Current knowledge on the functions of some of these 11 candidate genes are listed as the following the GNPAT is a dihydroxyacetonephosphateacyltransferase DHAPAT or DAPAT participating in the etherphospholipid biosynthesis Ofman et al 2001 the NOTCH4 is a heterodimer receptor involving in the vascular and articular cartilage development Hayes et al 2003 Iso et al 2003 the NRG1 neuregulin 1 is a group of isoform proteins produced from NRG1 gene by alternative splicing these isomers interact with ERBB receptor and induce the growth and differentiation of neuronal and glial cells Kerber et al 2003 Fallon et al 2004 The DAAO D-amino-acid oxidase is a peroxisomal enzyme activated by G72 D-amino acid oxidase activator Chumakov et al 2002 The CHRNA7 is a nicotinic acetylcholine receptor subunit belonging to the superfamily of ligand-gated ion channels and involving in the development of the central nervous system Agulhon et al 1999 Raux et al 2002 The PRODH proline dehydrogenase is an enzyme catalyzing proline to Δ-1-pyrroline-5-carboxylate P5C the first step in the conversion of proline to glutamate Harrison and Owen 2003 Lee et al 2003 Deletion of this gene has been associated with hyperprolinemia Jacquet et al 2002 The functional roles of these genes on the neuronal cells warrant further investigation to predict the possible pathological process for schizophrenia In this RIGOS project well use in vitro cell-line to do functional laboratory study to validate any of these risk mutations identified in this RIGOS project
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NSC-94-3112-B-002-020 | None | None | None |