Genetic dissection of multigenic disorders, such as schizophrenia, is truly challenging yet possible, particularly with the availability of the human genome sequence. Genomewide linkage scans in schizophrenia have suggested that susceptibility loci may be present on several chromosomes. It is possible that in founder populations there will be fewer susceptibility loci and alleles. In addition, founder populations often exhibit less environmental heterogeneity than do other populations and allow detailed genealogical research and reconstruction of extended multigenerational pedigrees. Availability of such large pedigrees should facilitate the detection of linkage. We have collected a large number of families with schizophrenia from the genetically isolated population of the Afrikaners from South Africa. We performed a 10-cM genomewide scan on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. The locus on chromosome 1 reached genomewide significance levels and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners. We propose to fine-map the chromosome 1p locus identified through the 10-cM genomewide scan of the Afrikaner family samples using microsatellite markers for a 1-cM coverage and SNPs for a denser coverage. We also propose to use genotypic information from the proband with the UPD to identify and define an Afrikaner risk haplotype on chromosome 1. In addition, we propose to perform a 10-cM genomewide scan in a second set of multiply affected Afrikaner families that we have collected to identify additional loci or strengthen the evidence and narrow the regions of involvement for already implicated loci. Finally, we propose to collect neurocognitive data from multiply affected Afrikaner families to use as quantitative endophenotypes of schizophrenia in a QTL linkage analysis.
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