A Positional Cloning Study on Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Observational

Summary: 
      This Group of Genomic Research in Psychiatric Disorders (GENOP) located at the Department of
      Psychiatry, College of Medicine and National Taiwan University Hospital (NTUH) had completed
      a serial psychopathological study of schizophrenia (SCH) defined by DSM-IV criteria. The
      results of this GENOP included: (1) delineating 2 to 3 subtypes of schizophrenia with
      prospective follow-up validity; (2) finding a trait marker of impaired attention measured by
      continuous performance test (CPT); (3) impaired executive function assess by Wisconsin Card
      Sorting Test (WCST) and impaired inhibition of P50 evoked potential; (4) five dinucleotide
      repeat polymorphism (DRP) markers in 5 different chromosomes with significant linkage scores,
      including D1S251 at 1q42.1, D6S296 at 6p22 , D8S1222 at 8p14, and D15S976 at 15q14, and
      D22S278 at 22q12; (5) finding a significant linkage of polymorphism marker located in a
      neurodevelopmental gene NOTCH4 ( 6p22); and neurophysiological function related gene CHNRA7
      (15q14); (6) successfully collected 700 multiplex families, collected by the collaboration
      between of NTUH, Taiwan - NIMH, USA in the Taiwan Schizophrenia Genetic Linkage Study (TSLS)
      project, with at least two siblings affected with schizophrenia in Taiwan. A genome-wide scan
      on this big sample will be completed recently in the laboratory of NIMH, U.S.A.. Around 300
      families had also CPT data in the whole family. This is probably the biggest number of
      multiplex families of a single ethnicity all over the world; (7) successfully setting up DNA
      and cell banks as well as clinical data bank. This substantial long track of this GENOP
      provided convincing background for this Positional Cloning Study on Schizophrenia (POCOS).

      Understanding the controversial results of current linkage study on SCH world-wide, this
      POCOS was designed to make a break through design in the study for locating and identifying
      the vulnerability genes of SCH by using (1) phenomenological subtypes; (2) endophenotype
      defined by impaired attention (CPT) and/or impaired executive function (WCST); (3) using
      large enough size of samples of a single ethnicity of Taiwanese family pedigrees.

      Major research tasks include (1) Linkage analysis and quantitative trait loci analysis, in
      collaboration with the team of Harvard Medical School, on the endophenotype defined by
      impaired attention and impaired executive function in 300 families with at least two siblings
      affected with SCH; (2) Two stages of genotyping, using High Throughput technology, of dense
      SNP markers, around DRP markers with significant linkage scores in the NTUH and TSLS studies,
      with average marker interval of 30kb in 3000 subjects of 700 multiplex families (a total of
      300 markers) for linkage and quantitative trait loci analysis; (3) Two stages of study on the
      polymorphisms and/or mutations of candidate genes using association study and TDT test. Each
      stage with 10 Candidate Genes in the NTUH and TSLS project, respectively. In the first stage,
      these are: (a) Neurodevelopmental related genes: DISC1, TRAX (1q42.1), NOTCH4 and TNF(6p21.3)
      and NT-3; (b) Neurotransmitter receptor genes of CHNRA7 (15q14) and NMDA related to attention
      impairment; (c) Neurotransmitter metabolizing enzyme gene COMT (22q11.2) related to impaired
      frontal lobe function; and (d) Pharmacology related genes of DRD3 and 5HTA2.
    

Detailed description: 
      1. Specific Aims This component project of positional cloning study of schizophrenia
           (POCOS) has two specific aims: (1) To locate and identify the vulnerability genes of the
           phenomenological phenotype as well as the endophenotypes of schizophrenia (SCH) at
           specific chromosome regions; (2) To find specific polymorphism of candidate genes
           associated with endophenotypes and/or phenomenological phenotypes of schizophrenia.
           These results will lead this POCOS team: (1) to develop new clinical diagnostic method
           and new prevention program including pharmacological agent in early intervention
           treatment of SCH for public health purpose; (2) to do functional genomic study on SCH;
           (3) to study the pathogenetic process of abnormal genes in abnormal neuropsychological
           and neurobiological functions of SCH; (4) to delineate the nature and the effect of
           gene-environmental interaction in the etiology of SCH.

           Up to the present time, all genome-wide scans for localization of vulnerability genes
           revealed no consistent results. The difficulty of molecular genetic study on
           schizophrenia is not the technology of molecular genetic study; It is the difficulty in
           clinical recruitment of adequate samples. Small sample size, diagnostic uncertainty, and
           multiple ethnicities of study samples were major reasons for this present unfruitful
           condition. This POCOS is designed with a remarkable strength of sample characteristics:
           (1) Using enough big sample size with DNA sample of around 700 families with at least
           two schizophrenic siblings. This family sample assures adequate power for linkage
           analysis and further positional cloning strategy, (2) Using standardized diagnostic
           assessment method for diagnosis assessment, including the Diagnostic Interview for
           Genetic Study (DIGS) and Medical Chart Records, (3) Using data of impaired attention and
           executive function for defining endophenotype of SCH in 300 families with at least two
           siblings affected with schizophrenia. These conditions make the design of this POCOS a
           break through in current molecular genetic study of SCH nowadays.

           The hypotheses to be tested are: (1) There are 3 to 5 vulnerability genes responsible
           for phenomenological schizophrenia, defined by DSM-IV criteria, locating in chromosome
           1q42, 6p22, 8p14, 15q14, 22q12 near markers DIS251, D6S296, D8S1222, D15S976, D22S278,
           respectively; (2) One vulnerability gene is responsible for endophenotype of
           schizophrenia, defined by impaired sustained attention assessed by continuous
           performance test (CPT); This responsible vulnerability gene may be located at chromosome
           15q14 near D15S976; (3) Different phenomenological subtypes of schizophrenia, including
           negative subtype, and non-negative subtype may have different lod scores in linkage
           analysis with specific genetic markers proposed in this study; (4) There are mutations
           and/or polymorphisms in the introns and/or exons of the candidate genes associated with
           the occurrence and/or specific subtypes of SCH.

        2. Background and Significance. Schizophrenia (SCH) is as devastating and stigmatized
           psychiatric disorder with brain pathology and high genetic loading. The patients usually
           become dependent on the family with great social cost. To locate and identify the
           vulnerability genes, to solve the social stigma, to design genetic counseling can bring
           a revolutionary development in psychiatry.

      This Genomic Study on Schizophrenia（GEMS）comprises of two complimentary component projects to
      do the positional cloning study on SCH (POCOS) and to do the psychological and genetic
      counseling study (POGES) in the same pool of families recruited for study. This component
      project ( NO.1), the POCOS is designed using a breakthrough approach to locate and identify
      vulnerability genes. The project of POGES (NO.2) is a humanity study complimentary to
      molecular genetic study and it is designed for exploring psychological issues related to
      stigma and genetic counseling of this devastating disease of Human Being.

        1. Genetic Basis of Schizophrenia Genetic epidemiological studies revealed that SCH is
           familial and the risk to first-degree relatives is approximately ten times the risk to
           relatives of controls (Tsuang et al., 1980, 1995; Guze et al., 1983; Kendler 1988).
           Monozygous twin pairs had concordance rates of 46%~53% and 14%~15% for dizygous twin
           pairs (Kendler KS 1983; Gottesman II 1993; Prescott and Gottesman II, 1993). The
           heritability was around 0.7. However, the concordance rate in MZ twins is far from 100%,
           the environmental factors should also be considered. The evidence of genetic
           contribution to the etiology of SCHwas further supported by adoption study (Heston 1966;
           Kety et al., 1968,1994; Kendler et al., 1994).

           Segregation analyses indicate that the model of multiple genes better fit the observed
           patterns of schizophrenia in family studies than do single major locus model (Faraone
           and Tsuang, 1985; Risch and Baron, 1984; Vogler et al., 1990). It was suggested that
           several genes (3 to 5 in number) in epistasis might responsible for genetic etiology of
           schizophrenia (Risch, 1990).

        2. Molecular Genetic Studies of Schizophrenia For linkage analysis, except the sex
           chromosomes (Delisi and Crow, 1989), there is no a priori hypothesis to focus on any
           given chromosomal region. The whole genome needs to be systemically screened. A few
           genome-wide scans of SCH for the decade found that many chromosome regions had
           suggestive evidences for linkage, including chromosome 1q21-q22, 1q31-q42, 2p22-q21,
           4q24-q32, 6p24-p22, 6q16-q23, 8p24-p21, 10p14-p13, 13q14-q32, 15q13-q14, 22q11-q13 (Coon
           et al., 1994; Shaw et al., 1998; Levinson et al.1998; Blouin et al., 1998; Kaufmann et
           al.1998; Faraone et al., 1998; Rees et al., 1999; Williams et al., 1999; Hovatta et al.,
           1999; Brzustowicz et al., 2000). However, only a few chromosome regions were ever
           reported to have genome-wide significant linkage evidences, including chromosome
           1q21-q22 (Brzustowicz et al.,, 2000), 6p24-p22 (Wang et al., 1995), 8p21 (Blouin et al.,
           1998), and 13q32 (Blouin et al., 1998).

           Another promising chromosome region is chromosome 1q 42. A balance translocation (1;
           11)(q42.1; q14.3) was associated with major mental illness including schizophrenia in a
           Scottish large family pedigree (St Clair et al., 1990). Two novel genes named DISC1
           (Disrupted in Schizophrenia 1) and DISC2 (Disrupted in Schizophrenia 2) at chromosome
           1q42.1 were disrupted at the breakpoint (Millar et al., 2000; 2001). This was confirmed
           in a Finnish family sample (Hovatta et al., 1999) and another study (Ekelund et al.,
           2001; Hwu et al, 2001).

           All these studies have shown a replication and non-replication pattern (Riley 2000). For
           detection of genes of modest effect in complex disorders, inadequate sample size and
           mixed ethnicity were major methodological problems. It is argued at least 600 hundred
           affected sib-pairs may be required for adequate power (Hauser et al., 1996).

           Candidate genes studies revealed inconsistent results in the past decade.
           Neurotransmitter related genes, such as dopamine (D1, D2, D3, D4, D5), serotonin,
           r-aminobutyric acid and Glutamate receptor genes had been studied using both association
           and linkage studies and no consistent results obtained (Asherson et al., 1995, Breyler
           et al, 1995; Hranilovic et al. 2000; Catalano et al., 1993, Serretti et al., 1999; Chen
           ACH, 1996,1997). Neuron growth related genes (Margolis et al., 1994), phospholipase
           genes (Peet, 1998, Wei 1998), and a potassium channel gene (hKCa3/KCNN3) (Dror et al.,
           1999) have been reported association with schizophrenia. In case-control design, many
           genes and phenotypes being evaluated and mixture of ethnicity in the sample may inflate
           the type I errors.

           Positional candidate gene approach using linkage dysequilibrium strategy may resolve the
           above two problems raised by the approach of candidate gene association study basing
           upon the previous linkage results to increase the prior probability and using
           parent-offspring trios as internal control. This approach is more powerful than linkage
           study to locate the susceptibility genes of complex disorder as schizophrenia (Risch and
           Merikangas, 1996). With the fine mapping linkage evidences, the whole genome sequence
           and single nucleotide polymorphism (SNP) map, and the advancing microarray technique
           available, this approach is more efficient to locate the susceptibility genes of
           schizophrenia, (Owen et al., 2000; Baron 2001). Recently, a study using above strategy
           has been reported significant linkage dysequilibrium evidence of schizophrenia to a
           microsatellite polymorphism and a SNP of a gene, NOTCH4 gene, at chromosome 6p21 (Wei
           and Hemmings, 2000).

           Considering the importance of adequate power for linkage analysis and the potentials of
           positional candidate gene approach using linkage dysequilibrium strategies, we propose
           this project to do positional cloning of vulnerability genes of schizophrenia. In this
           stage, we have collected the DNA sample of around 700 families with at least two
           schizophrenic siblings by our own efforts as well as through collaboration with Harvard
           University in these four years, and this family sample assures adequate power for
           linkage analysis and further positional cloning strategy.

        3. Neuropsychological Deficit in Schizophrenia SCH was fond to have impairment in
           neuropsychological functions of executive function, sustained attention and working
           memory (Goldberg and Gold, 1995) and was due to frontostriatal dysfunction (Elliot et
           al., 1995). Multiple impairment may be best demonstrated by test batteries, rather than
           single, isolated test (Kremen et al., 1994) andthe impairments strongly suggested
           dysfunction of frontal-temporal-limbic circuit (Gold and Harvey, 1993).

           Visual sustained attention by the Continuous Performance Test (CPT) and executive
           function by the Wisconsin Card Sorting Test (WCST) were studied more thoroughly. The
           more difficult ones are stable vulnerability indicators, while the simpler ones might be
           mediating vulnerability indicators in schizophrenia (Chen and Faraone, 2000). CPT
           deficits were associated with negative symptoms (Nuechterlein et al., 1986; Hain et al.,
           1993; Johnstone and Frith, 1996; Liu et al., 1997) and with thought disorder
           (Nuechterlein et al., 1986; Strauss et al., 1993; Nelson et al., 1998) or disorganized
           symptoms (Liu et al., 1997).

           Deficits in WCST performance were enduring and predicted long term disability,
           independent of other cognitive deficits (Weinberger et al., 1986; Goldberg et al.,
           1988). WCST deficits were found to be related to dorsolateral prefrontal cortex
           (Weinberger et al., 1986; Berman et al., 1995) and that the dopamimetic drugs improves
           its performance (Daniel et al., 1991; Mattay et al., 1996).

           These deficits, being found to be specific to SCH and with genetic risk of SCH, can thus
           serve as endophenotypes in genetic analysis on SCH.

        4. Endophenotype Approach in Molecular Genetic Studies of Schizophrenia To resolve the
           insufficient power of analyses and genetic heterogeneity of SCH, an alternative strategy
           was to use of a specific neurobiological characteristic of the illness as an
           endophenotype reflecting the effect of a single genetic alteration (Lander, 1988).

      The CPT deficit was a potential endophenotype of the genetic susceptibility to SCH (Chen and
      Faraone, 2000). It was present not only in SCH patients, but also in their non-psychotic
      relatives (Grove et al., 1991; Mirsky et al., 1995; Chen et al., 1998). Using data from 148
      non-psychotic relatives and 345 community adults, Chen et al. (1998) found that the
      recurrence risk ratio λwas greater than 15 for the undegraded CPT and greater than 30 for the
      degraded CPT.

      Thus, using CPT deficits as endophenotypes of SCH would provide a valuable measure of genetic
      risk, would improve the power of genetic analyses and may help identify susceptibility genes
      for schizophrenia. In our sample, around 220 families have received CPT and WCST assessment.
      We intent to add 80 families with CPT and WCST data, and to make a 300 of families with
      available data for endophenotype study. It is feasible to use these endophenotypes for
      further genetic analysis.

      This endophenotype strategy has been successful in mapping of a neurophysiological deficit of
      schizophrenia, decrease of P50 inhibition, to loci at chromosome 15q13-14, recently. The
      genome-wide linkage analysis of the P50 inhibition deficit in nine multiplex SCH families
      found a significant lod score (Z = 5.30,  = 0) at a loci chromosome 15q14. When the clinical
      diagnosis of SCH was used as the affected phenotype, the maximum lod score at the same marker
      was not statistically significant (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 4.02. Again, while the clinical diagnosis of schizophrenia
      was used as the affected phenotype, the linkage result was non-significant (Arolt et al.,
      1996). In summary, with the endophenotype approach using sustained attention deficits and the
      adequate power our sample provides, we have confidences in the breakthrough of the searching
      for vulnerability genes of SCH.

      Preliminary Studies.

      1. Collection of Schizophrenia Co-affected Sibpairs Family The P.I. has been committed
      himself in collecting the schizophrenia co-affected sib-pairs family since 1990. With the
      awareness of the importance and critical necessity of diagnostic assessment, these probands,
      co-affected sib and available non-affected sib as well as the parents were assessed with a
      semi-structured psychiatrist diagnostic interview (Hwu 1991a) using diagnostic criteria of
      DSM-III-R and/or DSM-IV. Besides, under the evolutionary theoretical model of psychopathology
      (Hwu 1985, 1992), developmental data were also collected. All these clinical data and
      family-tree data were established in the data bank of the molecular genetic laboratory
      (DBMGL) in the Department of Psychiatry, College of Medicine, National Taiwan University
      under the auspice of the P.I. In total, there are around 120 schizophrenia co-affected
      sib-pairs families available for linkage analysis in the DBMGL. As a rule, the DNA samples
      were obtained from the peripheral white cells of all available subjects of the family,
      especially the co-affected sibs, at least one non-affected sib and the parents. In total,
      around 1000 DNA samples were in the DBMGL. Cell-lines of EBV-958 transformed lymphoblast
      cells were established too. All these study subjects were well informed for this study and
      informed consent obtained. All families participated in this study were invited to join a "
      New-Hope Family Club" for periodic meeting and discussion. Around 150 schizophrenia cases who
      received detail clinical assessment and regular follow-up and comprehensive
      neuropsychological assessment, including CPT, WCST, WAIS-R, and WMS, were recruited for
      obtaining DNA samples. Around 200 normal control subjects were also recruited for obtaining
      DNA samples.

      A 4-year nation-wide collaborative work with Harvard University in Taiwan (Taiwan
      Schizophrenia Linkage Study, TSLS), sponsored by the NIMH, U.S.A., to collect families with
      co-affected sib-pairs with schizophrenia has been completed. 560 families have been
      recruited. A total of 600 families will be recruited in this year. DNA samples, cell-lines
      and clinical data of DIGS, FIGS were collected. Around 220 families received
      neuropsychological evaluation. (CPT and WCST).

        1. Molecular Genetic Studies of Schizophrenia Our molecular genetic studies of
           schizophrenia were supported by three consecutive projects: the molecular genetic
           project sponsored by the National Science Council (1989-1992), the molecular genetic
           project of MPGRP (1993-1998) and the molecular genetic project of MPSS (1998-2001)
           sponsored by NHRI. The early phase (1989-1992) of this molecular genetic project focused
           on establishing laboratory facilities and collecting co-affected schizophrenic sib-pair
           families. The 2nd phase of this molecular genetic project (1993-1998) continued the
           collection of families, and the collection was extended to collect the co-affected
           bipolar sib-pairs, schizophrenic cases and normal controls. We found the polymorphism of
           androgen receptor gene of (CAG)n had a probable association with schizophrenia (Hwu et
           al., 1995). This finding supported the finding of DeLisi et al (1994). The molecular
           genetic methods of linkage analysis and candidate gene association were promoted, this
           laboratory of the P.I. (Dr. Hwu) moved to emphasize in this area too. The results of
           this laboratory were: (1) The polymorphism of (48bp) repeats in DRD4 receptor gene was
           not significantly linked with schizophrenia (Hong et al., 1998); (2) A single mutation
           in DRD2 was found not to be associated with schizophrenia (Chen et al.,1996) (3) The
           samples of the data bank of this project had joined three international collaboration
           studies using positional cloning approach which need relatively large sample. The one is
           organized by Gill et al (1996) entitled as "Schizophrenia Collaborative Linkage Group",
           another was led by Dr. Moises (1995) in Kiel University, Germany and the third one is
           with Dr. Powell in London (Lin et al., 1995). All these results revealed the possible
           markers in chromosomes 6p, 11q, 13q, 19q and 22q. This suggests that Taiwanese patients
           may have possible susceptibility genes in these regions, except chromosome 13q (Lin et
           al., 1995), fitting an oligogenetic model. (4) The association study on 5-HT2 receptor
           gene located on chromosome 13q was found to be negative; (5) Clinical epidemiological
           analysis using co-affected sib-pairs demonstrated the tendency of 3 independent symptom
           clusters of reality disorganization, disorganization and negative state (Hwu et al.,
           1997); (6) Weak linkage evidence to loci at chromosome 6p24-22 (Hwu et al.,2000).

           The 3rd phase of the molecular genetic study (1998-2001) continued focusing at
           collecting co-affected schizophrenic sib-pair families and linkage analysis on reported
           suggestive evidences of chromosome regions, including chromosome 1q21-q22, 1q31-q42,
           6p21, 8p24-p21, 15q13-q14, 22q11-q14. The linkage results were (1) suggestive evidence
           of linkage for schizophrenia with and without the negative symptoms on chromosome 6p24
           and 22q12 (Lin et al., 1999a) (2) no linkage evidence of GABAA receptor α1 (GABRA1), β1
           (GABRB1) andβ3 (GABAB3) subunit gene with schizophrenia (Lin et al., 1999b) (3) no
           linkage evidence of Glutamate GluR5 and GluR6 receptor gene with schizophrenia (Lin et
           al., 1999c) (4) no linkage evidence of SCA1 gene with schizophrenia (Liu et al., 2001a)
           (5) suggestive linkage evidence on marker (D8s1222) of chromosome 8p with schizophrenia
           (NPL Z score = 2.58, p=0.005) (Hwu et al., 2001a) (6) suggestive linkage evidence of
           marker (D1s251) of chromosome 1q31-42 with schizophrenia (NPL Z score = 2.18, p=0.01)
           (Hwu et al., 2001b), The marker is located near the DISC1 candidate gene. (7) suggestive
           linkage evidence of marker (D15s976) on 15q13-14 with schizophrenia (NPL Z score = 3.33,
           p=0.0003) (Liu et al., 2001b). (8) no linkage evidence of schizophrenia to loci at
           chromosome 1q21-22 (Liu et al., 2001c). (9) Suggestive linkage to NOTCH4 gene locus at
           chromosome 6p21.3 (NPL Z score = 2.79, p=0.002) (Hwu et al. 2001c). The candidate gene
           approach has revealed the following results: (1) possible association between Dopamine
           D4 receptor (DRD4) gene polymorphism with quick treatment response of schizophrenia (Liu
           et al., 2001d). (2) no association between cytosolic phospholipase A2 (c-PLA2) gene
           polymorphism and schizophrenia (Liu et al., 2000).

        2. Studies on Neuropsychological Deficits in Schizophrenia We found impaired sustained
           attention by continuous performance test (CPT) as the trait marker of schizophrenia.
           Family studies have indicated that sustained attention deficits as measured by the CPT
           are vulnerability markers of schizophrenia (Chen and Faraone, 2000). The results are:
           (1) a substantial proportion of non-psychotic relatives of schizophrenia probands
           (19-34%) have CPT deficits, which can be predicted from their probands' CPT performance
           (Chen et al., 1998a); (2) subjects with schizotypal personality features also exhibit
           CPT deficits, which are specifically associated with negative factors of schizotypy.
           (Chen et al., 1998b); (3) CPT deficits are present in schizophrenic patients, are
           particularly associated with negative and disorganized symptoms, and those with more
           difficult CPT versions are not amenable to neuroleptic treatment (Liu et al., 2000).

           The specificity of CPT was studied (Liu et al., 2000) in a group of schizophrenia
           patients (n=41) in contrast to the group of bipolar patients with psychotic symptoms
           (n=46) and the group of bipolar patients without psychotic symptoms (n=22) and a group
           of patients with non-psychotic major depressive disorder (n=22). It was found that CPT
           deficits are stable vulnerable indicators of schizophrenia, mediating vulnerability
           indicators for bipolar disorder, and state-dependent indicator for major depression.
           These results demonstrate that CPT deficits are valid trait marker of schizophrenia.

        3. Studies on Clinical Heterogeneity of Schizophrenia In the field of psychiatry, clinical
           psychopathological background is crucial for molecular genetic studies. The principal
           investigator (HGH) had developed an evolutionary psychopathological theoretical model
           for descriptive as well as neurobiological studies. The complete work of the descriptive
           psychopathological study on schizophrenia was published [Schizophrenia: a descriptive
           psychopathology, 1999 ISBN 957-9201-21-8, Taipei, Chu-ching Publishing Company]. The
           clinical heterogeneity issue has been approached by a novel statistical method using
           graphic plotting technology (Chen, 1999) based on PANSS rating scale. Two (Hwu et al,
           2001) or three (Hwu et al, 2001) subtypes of schizophrenia were delineated and validated
           by follow-up and neuropsychological data such as attention impairment (CPT). Through
           two-year follow-up, the symptom patterns of schizophrenic patients were stable (Hwu et
           al, 2001). This confirms the subtyping efforts in schizophrenia using phenomenological
           symptom patterns. These data suggest the possible fruitfulness of genetic linkage study
           on schizophrenia considering the phenomenological subtypes as well as endophenotypes in
           linkage as well as association studies.

      In conclusion, all these preliminary data reveal that the DNA sample, clinical and
      endophenotype data have been well prepared in this POCOS program. The PI and his team are
      experienced in performing the laboratory work and further genetic analysis in this project.
    

Observational model: Defined Population
Time perspective: Other
Keywords: schizophrenia; vulnerability gene; positional cloning; subtype definition; endophenotype; genetic marker; genetic linkage; candidate genes