This is a revised four-year competing continuation proposal for collaborative linkage and association studies of schizophrenia in a multicenter sample of 860 informative pedigrees under a narrow diagnostic model. Four of seven sites are participating as Collaborative R01s (Penn, Hopkins, Northwestern, VCU), and three sites (U. Wales, U. Paris VI, U. W. Australia) as consortia to the University of Pennsylvania. The investigators' meta-analysis of 20 schizophrenia genome scans identified a set of regions with significant evidence for linkage across scans. Linkage and association data from large samples can narrow the candidate regions and facilitate the identification of susceptibility genes and their interactions. ? A new 6 cM microsatellite genome scan will be carried out using 605 markers. The Center for Inherited Disease Research (CIDR) will type 388 markers so that data can be readily integrated with two other large ongoing schizophrenia genome scans for a total of over 2,000 pedigrees. The Australian Genome Research Facility will type an additional 217 markers from high-density screening maps, selected to form the most evenly-spaced 6 cM map when combined with the CIDR map. A denser map can increase the power of the proposed analyses of linkage and of interactions between loci. Dimensional psychopathology ratings will also be completed for the entire sample and utilized in genetic analyses. Linkage fine-mapping studies of the best candidate regions will be undertaken using 2 cM microsatellite maps to maximize linkage information and to narrow the one-lod support interval in each region. One or more regions with evidence for linkage in this sample and in our schizophrenia genome scan meta-analysis will be selected for LD mapping studies (lllumina) to identify specific positional candidate genes. Carrying out these studies in a large multiplex pedigree sample bypasses the problem of population stratification and permits analyses of whether the evidence for association in a linked region also explains the linkage signal. Candidate gene replication studies will also be carried out to assess emerging findings in the field. Genotypes from the genome scan, LD mapping and replication studies will be made publicly available along with diagnoses and dimensional psychopathology ratings and factor scores. In response to reviewers' suggestions, this revised application includes a reduction in genotyping costs, centralization of most of the genotyping of microsatellite and SNP markers in high-throughput labs to improve quality control and efficiency, and improvement of the dimensional clinical rating component. ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-G (90))
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Lehner, Thomas
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Virginia Commonwealth University
Schools of Medicine
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Franke, Barbara; Stein, Jason L; Ripke, Stephan et al. (2016) Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci 19:420-431
Edwards, Alexis C; Bigdeli, Tim B; Docherty, Anna R et al. (2016) Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes. Schizophr Bull 42:279-87
Docherty, Anna R; Bigdeli, T Bernard; Edwards, Alexis C et al. (2015) Genome-wide gene pathway analysis of psychotic illness symptom dimensions based on a new schizophrenia-specific model of the OPCRIT. Schizophr Res 164:181-6
Bigdeli, T Bernard; Bacanu, Silviu-Alin; Webb, Bradley T et al. (2014) Molecular validation of the schizophrenia spectrum. Schizophr Bull 40:60-5
Zhao, Zhongming; Webb, Bradley T; Jia, Peilin et al. (2013) Association study of 167 candidate genes for schizophrenia selected by a multi-domain evidence-based prioritization algorithm and neurodevelopmental hypothesis. PLoS One 8:e67776
Fanous, Ayman H; Amdur, Richard L; O'Neill, Francis A et al. (2012) Concordance between chart review and structured interview assessments of schizophrenic symptoms. Compr Psychiatry 53:275-9
Levinson, Douglas F; Shi, Jianxin; Wang, Kai et al. (2012) Genome-wide association study of multiplex schizophrenia pedigrees. Am J Psychiatry 169:963-73
Bigdeli, T Bernard; Maher, Brion S; Zhao, Zhongming et al. (2011) Comprehensive gene-based association study of a chromosome 20 linked region implicates novel risk loci for depressive symptoms in psychotic illness. PLoS One 6:e21440
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43:969-76
Thiselton, D L; Maher, B S; Webb, B T et al. (2010) Association analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS). Am J Med Genet B Neuropsychiatr Genet 153B:323-31

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