Family, twin and adoption studies have consistently shown that genetic factors are of major etiologic importance in schizophrenia. Since early in this century, it has been suggested that there are single genes of """"""""major effect"""""""" for schizophrenia. Recent advances in molecular biology and in statistical approaches to linkage analysis now provide us, for the first time, with the techniques to rigorously evaluate this claim. This is a proposal to conduct linkage analyses on a large number of multiplex pedigrees for schizophrenia that are currently being ascertained and sampled in Ireland (MH-41953). This study will utilize the abundant, highly polymorphic DNA markers that have recently become available to span virtually the entire human genome as well as potential candidate genes. This proposal seeks to capitalize on the unique resource of high density Irish schizophrenic pedigrees that include: i) a relatively homogeneous ethnic composition of the population, which should reduce the problems of genetic heterogeneity; ii) enhanced ability to determine optimal diagnostic criteria, and estimates of gene frequency and penetrance necessary for linkage analyses by utilizing data obtained from a large sample epidemiologically based family study currently nearing completion in the West of Ireland and iii) the close genetic relationship between Ireland and both Iceland and England, the countries in which pedigrees have been ascertained that demonstrate significant linkage to markers on chromosome 5. Genetic markers throughout the genome will be typed for the high density schizophrenic families, first concentrating in areas that previous studies suggest might be of potential relevance to schizophrenia. Several distinct statistical methodologies of segregation and linkage analysis will be applied to the data in order to fully utilize their potential. Any strong positive findings will be pursued by cloning additional markers from that part of the genome where a major locus for schizophrenia might lie, in order to map the locus more precisely.

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National Institute of Mental Health (NIMH)
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Psychopathology and Clinical Biology Research Review Committee (PCB)
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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, 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, 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; 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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