Expanding Rapid Ascertainment Networks of Schizophrenia Families in Taiwan
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Observational

Summary: 
      This proposal responds to Request for Applications RFA ( Rapid Founding Award)-MH ( Mental
      Health)-08-131, which seeks applications that propose to enrich pre-existing resources for
      schizophrenia in the NIMH ( National Institute of Mental Health) Human Genetics Initiative
      and to apply genomic methods to further our understanding of the molecular etiology of the
      disorder. The overarching aims of this proposal are to quickly and cost-effectively ascertain
      a large sample of trio families affected by schizophrenia, and to discover causal variants
      for the disorder in the first family-based genome-wide association study (GWAS) of the
      disorder. In Taiwan, there is no such kind of policy to support this kind of GWAS study as it
      is a very expensive study, including collecting large family samples and genome-wide SNP
      scanning. We, thus, collaborate with Professor Ming T, Tsuang and his extended subcontracted
      researchers to apply for this project. We, the research team in Taiwan, will collect 3800
      trio families (11400 subjects) of schizophrenia. In our recently completed NIMH-funded
      Genetic Linkage Study of Schizophrenia (R01MH059624; USA PI: Ming T. Tsuang; Taiwan PI:
      Hai-Gwo Hwu), the investigators established a large and efficient ascertainment network and
      infrastructure in Taiwan, which will again be utilized and expanded in the proposed study.
      Through additional ascertainment within this framework, the investigators will collect an
      aggregate sample with adequate power for detecting in a GWAS those variants that make even
      small contributions to the risk for the disorder.

      The investigators will meet the overarching goals of this project by accomplishing several
      Specific Aims, as follows:

        1. Rapidly ascertain schizophrenia trio families from ten Taiwanese clinical ascertainment
           sites;

        2. Supplement NIMH Genetics Initiative collections by sending all clinical data and
           biomaterials to the appropriate repositories;

        3. Assess the association of schizophrenia with a genome-wide panel of single-nucleotide
           polymorphisms (SNPs) and their constituent haplotypes;

        4. Analyze quantitative schizophrenia phenotypes such as age at onset ;

        5. Perform a genome-wide survey for copy-number variations related to schizophrenia;

        6. Test for gene-gene interactions (epistasis); and

        7. Test for gene-environment interactions, such as the well-established effect of season of
           birth.
    

Detailed description: 
      Over the past four decades, researchers have become increasingly certain that schizophrenia
      has a complex, multifactorial etiology. Although many twin studies confirm that genes play a
      substantial role in the etiology of this disabling disorder,5 genome-wide linkage analysis of
      schizophrenia have produced conflicting results. While many of these studies have identified
      chromosomal regions showing some evidence for linkage to schizophrenia, no finding has been
      consistently replicated. Given the high heritability of schizophrenia,5 the failure of
      linkage methods to find susceptibility genes suggests that these genes each have very small,
      incremental effects on the expression of the disorder. Risch and Merikangas6 showed that for
      genes of small effect, the power of linkage studies will be low but the power of association
      studies will be high. Although meta-analysis of candidate gene association studies have
      implicated some genes, these findings (even if confirmed by larger studies) would only
      account for a small fraction of schizophrenia's heritability. These considerations suggest
      that a genome-wide association scan would be an effective method for finding schizophrenia
      susceptibility genes. To that end, the investigators have designed a multi-stage analytic
      plan which involves rapid continued ascertainment of probands and family members from an
      established clinical ascertainment network in Taiwan, performing a genome-wide association
      scan (GWAS) on this large sample of affected nuclear families, and pooling the novel GWAS
      results from this project with those from existing case-control GWAS studies of
      schizophrenia. To accomplish these objectives, the investigators propose a series of specific
      aims, as follows:

        1. Supplement our previously collected sample of 1,200 Han Chinese schizophrenia-affected
           nuclear families from Taiwan by rapidly screening and collecting an additional 3,800
           trios from eleven ascertainment sites in Taiwan;

        2. Assess the association of schizophrenia with a genome-wide panel of single-nucleotide
           polymorphisms (SNPs) and their constituent haplotypes;

        3. Perform a genome-wide survey for copy-number variations related to schizophrenia;

        4. Test for gene-gene interactions and epistasis;

        5. Test for gene-environment interactions, such as the well-established effect of season of
           birth;

        6. Analyze quantitative schizophrenia phenotypes, such as age at onset; and

        7. Enhance the NIMH Genetics Initiative collections by sending all clinical data,
           biomaterials, and genotypes to the appropriate repositories, and completing a
           meta-analysis of our family-based GWAS data and those from existing case-control GWASs
           of schizophrenia in the repository;

      The above aims achieve the goals of the RFA in several ways. First, the proposed work would
      markedly enrich the existing resources of the NIMH Human Genetics Initiative, especially the
      current pool of schizophrenia-affected nuclear families. Not only would the data and
      biomaterials from this project enrich the NIMH repositories, the study has been designed to
      be readily combinable with those already in the repositories to boost the power available for
      detecting genes with small effects on risk. Further, the proposed project would apply the
      latest genomic research methods to further our understanding of the molecular etiology of the
      disorder. Lastly, by capitalizing on an existing clinical infrastructure and an efficient
      screening and assessment protocol, the investigators will obtain a well-powered sample in a
      very rapid and cost-effective manner.
    

Observational model: Family-Based
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        schizophrenia Han Chinese Population one sibling with his/her parents
      
Biospecimen description: 
      Whole blood.
    
Keywords: schizophrenia; genome-wide association study (GWAS); single-nucleotide polymorphisms (SNPs); Han Chinese population; trio families; Schizophrenia with trio families