Mapping Gene for Schizophrenia in Founder Population

描述（由申请人提供）：多基因疾病（如精神分裂症）的遗传解剖确实具有挑战性，但也是可能的，特别是在人类基因组序列可用的情况下。精神分裂症的全基因组连锁扫描表明，易感基因座可能存在于几条染色体上。在创始人群中，易感基因座和等位基因可能会更少。此外，创始人群体往往表现出较少的环境异质性比其他人群，并允许详细的系谱研究和重建扩展的多代系谱。这样大的谱系的可用性应有助于连锁的检测。 我们收集了大量的家庭精神分裂症的遗传隔离人口的南非白人。我们对143个小家族进行了10 cM的全基因组扫描，其中34个为连锁提供了信息。使用非参数和参数连锁分析，我们获得的证据，少数疾病位点的染色体1，9和13。1号染色体上的位点达到全基因组显著水平，代表了精神分裂症的一个新的易感位点。除了提供1号染色体连锁的证据外，我们还发现了一个先证者，其整个1号染色体为单亲二体（UPD）。这是第一次在精神分裂症患者中描述UPD，进一步支持1号染色体参与南非白人精神分裂症易感性。 我们建议精细映射的染色体1p位点确定通过10厘米的全基因组扫描的南非白人家庭样本使用微卫星标记的1厘米的覆盖范围和SNPs的更密集的覆盖范围。我们还建议使用基因型信息的先证者与UPD确定和定义一个南非白人风险单倍型1号染色体上。此外，我们建议进行10厘米的全基因组扫描，在第二组多重影响的南非白人家庭，我们已经收集到的，以确定额外的基因座或加强证据，并缩小区域的参与已经牵连的基因座。最后，我们建议收集神经认知数据，从多重影响的南非白人家庭使用的数量内表型的精神分裂症的QTL连锁分析。

DESCRIPTION (provided by applicant): 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.