Supported by previous funding of this project, we have demonstrated suggestive linkage for schizophrenia susceptibility on chromosome 6p22-p24 in the 270 multiplex families from the Irish Study of High Density Schizophrenia Families (ISHDSF). These findings have been supported by data from numerous independent samples of multiplex schizophrenia families using different study designs, and by a collaborative multicenter study. Furthermore, we recently identified a set of SNP markers in a novel gene that give highly significant evidence of association with schizophrenia susceptibility in this sample and identified this gene (dystrobrevin binding protein 1, DTNBP1) as the human ortholog of mouse dysbindin or Dtnbp1) Association with this gene has been replicated by a number of groups using different study designs. Analyses of the current data show significant excess transmission of a haplotype of 8 markers in both the Irish pedigrees and in a sample of 79 sib-pair families from Germany and Israel and 128 trios from Germany. The specific overtransmitted haplotype is different in these two samples. None of the SNP variants so far tested have any predicted functional role. We argue below that current data strongly support two hypotheses: 1) that the haplotype region contains pathogenic variant(s) and 2) that these variant(s) impact on schizophrenia liability. The identification of the relatively rare Irish high risk haplotype (HRH), a more common overtransmitted haplotype in the German sample, and the overall haplotype block structure of the region allow us to define specific-haplotype-based cases in both samples for screening and allow us to map variation back to specific haplotypes. We also argue below that collaborative work in these 2 samples yields two benefits: additional power both for variant detection and subsequent analysis and an essential control group for such specific-haplotype-based variation screening. In this competitive renewal, we request 5 further years of support with the primary goals of identifying these pathogenic variant(s) and relating them to the biology of the gene, gene product and disease.
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