Haplotype and Expression Mapping of Prepulse Inhibition

描述（由申请人提供）： 惊吓前脉冲抑制（PPI）是精神分裂症患者受损的一种神经生理学特征，并且在近交系小鼠品系之间存在差异。我们已经研究了来自C57 BL/6 J和A/J小鼠的染色体置换小鼠品系（consomic品系），以鉴定具有PPI数量性状位点（QTL）的染色体，并获得了小鼠16号染色体上存在一个或多个PPI基因的证据。自我们最初的申请，我们已经迅速完成了互交作图，使我们能够确定两个显着的PPI QTL 16号染色体（LOD = 3.9和4.6），分别为3.5 cM和5.5 cM的大小。我们建议使用多方面的方法，结合近交系单倍型定位和mRNA表达谱来识别小鼠16号染色体PPI基因。我们将首先使用已知PPI不同的多个近交系小鼠品系的单倍型作图来细化16号染色体QTL。与此同时，我们将进行小鼠的回交分离每个染色体16 QTL和测试重组近交系的PPI，以帮助完善的基因座。然后，我们将在C57 BL/6 J和16号染色体置换株中进行相关脑区域的mRNA表达研究，以确定差异表达的基因作为候选PPI基因。这些数据将被翻译到我们实验室正在进行的人类研究中，以确定候选小鼠PPI基因的直系同源物是否与人类PPI或精神分裂症风险有关。我们将通过构建人类单倍型图谱的候选PPI基因确定的定位和分析，然后测试与精神分裂症和PPI在我们的患者样本中的关联来实现这一目标。这项建议是一项初步研究，以确定涉及PPI和精神分裂症的基因，也是一个原则证明，这种多方面的方法可以广泛适用于复杂的人类特征的研究。

DESCRIPTION (provided by applicant): Prepulse inhibition of startle (PPI) is a neurophysiological trait that is impaired in schizophrenia patients and varies among inbred mouse strains. We have studied chromosome substitution mouse strains (consomic strains) derived from C57BL/6J and A/J mice to identify chromosomes that harbor PPI quantitative trait loci (QTLs), and have obtained evidence for one or more PPI genes on mouse chromosome 16. Since our original application, we have rapidly completed intercross mapping, allowing us to identify two significant PPI QTLs on chromosome 16 (LODs = 3.9 and 4.6) that are 3.5 cM and 5.5 cM in size. We propose to identify the mouse chromosome 16 PPI genes using a multi-faceted approach that incorporates inbred strain haplotype mapping and mRNA expression profiling. We will first refine the chromosome 16 QTLs using haplotype mapping across multiple inbred mouse strains known to vary in PPI. In parallel, we will perform backcrosses of mice segregating each chromosome 16 QTL and test recombinant inbred strains for PPI to assist in refining the loci. We will then perform mRNA expression studies of relevant brain regions in the C57BL/6J and chromosome 16 substitution strains to identify differentially expressed genes as candidate PPI genes. These data will be translated into the human studies ongoing in our lab to determine whether the orthologs of the candidate mouse PPI genes are involved in human PPI or schizophrenia risk. We will carry out this aim by constructing human haplotype maps of candidate PPI genes identified by mapping and profiling, and then testing for association with schizophrenia and PPI in our patient samples. This proposal is a pilot study to identify genes involved in PPI and perhaps schizophrenia, and is also a proof-of-principle that this multi-faceted approach could be widely applicable to the study of complex human traits.