This is a revised competing renewal application for two additional years of funding for a genome mapping study of schizophrenia. Schizophrenia causes severe disability in about 1% of the population. There is evidence for a predominantly genetic etiology. Rigorous completion of a number of genome scan studies of schizophrenia may permit the identification of chromosomal locations of susceptibility genes, and then lead to characterization of specific pathogenic defects and mechanisms. The applicant and his team of investigators have completed a genome scan using a 335-marker (10cM) map and multipoint Non-Parametric Linkage analysis of 45 multiplex pedigrees (2-5 affected per pedigree), and have collected 22 additional pedigrees for the proposed additional genotyping. The sample is a collaborative effort of four groups (Allegheny University, University of Queensland, University of Iowa, Mt. Sinai). There are 131 affected individuals by an intermediate diagnostic model (DSM-IIIR) schizophrenia, schizoaffective, schizophreniform and other non-affective psychotic disorders.) Linkage analysis data are presented. Regions have been identified that deserve additional study. These regions have positive NPL scores across a series of markers and peak scores that exceed a threshold of p < 0.05. Continued funding is requested to: 1) genotype a denser map in the expanded sample of 67 pedigrees in the most positive regions from the completed genome scan; 2) collaborate with the NIMH Clinical Neurogenetics Branch to follow up positive findings from each other's scans (which use the same screening map and diagnostic model); 3) participate in international collaborative efforts to follow up findings from other studies; 4) continue the collection of pedigrees (primarily in Australia, with only a small portion of the needed funding to come from the present grant) to continue to build the sample size in the proposed work for future studies and for collaborative investigations.
| Holliday, Elizabeth G; Handoko, Herlina Y; James, Michael R et al. (2006) Association study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples. Twin Res Hum Genet 9:531-9 |
| Lewis, Cathryn M; Levinson, Douglas F; Wise, Lesley H et al. (2003) Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 73:34-48 |
| Levinson, D F; Kirby, A; Slepner, S et al. (2001) Simulation studies of detection of a complex disease in a partially isolated population. Am J Med Genet 105:65-70 |
| Levinson, D F (1993) Power to detect linkage with heterogeneity in samples of small nuclear families. Am J Med Genet 48:94-102 |
| Levinson, D F; Mowry, B J (1991) Defining the schizophrenia spectrum: issues for genetic linkage studies. Schizophr Bull 17:491-514 |
