A number of different lines of evidence suggest a strong role for heredity in the etiology of schizophrenia, a relatively common, chronic and debilitating psychiatric disorder. Linkage and association studies, however, have not to date been successful in elucidating the underlying genetic mechanisms. We request in this application five years of continued support to detect, localize and characterize susceptibility genes contributing to schizophrenia. This work will be performed using data from the recently completed Irish Study of High Density Schizophrenia Families (ISHDSF). The ISHDSF was derived from a systematic ascertainment of multiplex schizophrenia pedigrees in 37 facilities covering over 90% of the relatively homogeneous population of Ireland and Northern Ireland. The linkage sample contains 264 pedigrees and DNA from 1,404 individuals. The primary specific aim of this project is to complete a systematic genome scan of the ISHDSF by using highly polymorphic DNA markers located approximately every 10 centimorgans. Follow-up genotyping will be performed in genomic regions showing preliminary evidence of linkage. Statistical analyses will be performed using standard parametric and nonparametric methods, as well as by techniques recently developed by our group that may increase power to detect linkage for complex traits such as schizophrenia.
A second aim i s to test genes in these regions of possible linkage, i.e., """"""""positional"""""""" candidate genes, to identify which gene(s) in the region is producing the linkage signal. Integrating I) a large, systematically gathered and carefully characterized clinical sample, ii) both standard and novel statistical methods and iii) the latest genomic and molecular genetic techniques, which includes automation and utilization of the methods and reagents supplied by the Human Genome Project, this proposal provides a realistic opportunity to overcome the difficulties with prior studies and successfully identify and characterize genes that significantly influence the susceptibility to schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Virginia Commonwealth University
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Fanous, A H; Zhao, Z; van den Oord, E J C G et al. (2010) Association study of SNAP25 and schizophrenia in Irish family and case-control samples. Am J Med Genet B Neuropsychiatr Genet 153B:663-674
Fanous, Ayman H; Chen, Xiangning; Wang, Xu et al. (2009) Genetic variation in the serotonin 2A receptor and suicidal ideation in a sample of 270 Irish high-density schizophrenia families. Am J Med Genet B Neuropsychiatr Genet 150B:411-7
Fanous, Ayman H; Neale, Michael C; Webb, Bradley T et al. (2008) Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families. Biol Psychiatry 64:121-7
Fanous, A H; Neale, M C; Gardner, C O et al. (2007) Significant correlation in linkage signals from genome-wide scans of schizophrenia and schizotypy. Mol Psychiatry 12:958-65
Fanous, Ayman H; Chen, Xiangning; Wang, Xu et al. (2007) Association between the 5q31.1 gene neurogenin1 and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 144B:207-14
Fanous, Ayman H; Neale, Michael C; Webb, B Todd et al. (2007) A genome-wide scan for modifier loci in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 144B:589-95
Fanous, Ayman H; van den Oord, Edwin J; Riley, Brien P et al. (2005) Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. Am J Psychiatry 162:1824-32
Fanous, A H; Kendler, K S (2005) Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry 10:6-13
Fanous, Ayman H; Kendler, Kenneth S (2004) The genetic relationship of personality to major depression and schizophrenia. Neurotox Res 6:43-50
Sullivan, Patrick F; Walsh, Dermot; O'Neill, F Anthony et al. (2004) Evaluation of genetic substructure in the Irish Study of High-Density Schizophrenia Families. Psychiatr Genet 14:187-9

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