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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH068921-01A1
Application #
6782226
Study Section
Special Emphasis Panel (ZRG1-SSS-G (90))
Program Officer
Moldin, Steven Owen
Project Start
2004-06-01
Project End
2008-04-30
Budget Start
2004-06-01
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$167,625
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Levinson, Douglas F; Shi, Jianxin; Wang, Kai et al. (2012) Genome-wide association study of multiplex schizophrenia pedigrees. Am J Psychiatry 169:963-73
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet 43:969-76
Ng, M Y M; Levinson, D F; Faraone, S V et al. (2009) Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol Psychiatry 14:774-85
Holmans, P A; Riley, B; Pulver, A E et al. (2009) Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms. Mol Psychiatry 14:786-95