Project 1

大规模群体遗传学研究已经开始绘制精神分裂症（SZ）的遗传结构图。我们 现在我知道，这种多因素性状的遗传贡献来自各种病变，包括a） 强效应的罕见拷贝数变体（CNV）; B）轻度效应的常见非编码等位基因;和c）罕见 编码聚集在生物模块中的等位基因。我们最近的研究使我们有机会 综合遗传学、基因组学和功能学研究，剖析微管和纤毛的作用。 并开发生理学相关的测定来询问基因和等位基因的作用 作为一种增强统计能力的手段。在这里，我们将继续关注一个特定的生物模块， 调节微管功能的蛋白质簇，因为其涉及轴突/树突生长和纤毛功能，以及 从CNV病理机制、调控突变和罕见的 大的影响。我们处于独特的位置来衡量这个模块对深圳的贡献。首先，我们将提高我们的 了解16p11.2 CNV病理学，这是SZ最重要的贡献者之一;从 利用我们小组以及项目2、3和核心C的专业知识，我们将检验贡献假设 对于KCTD 13，我们和其他人已经积累了强大的，但间接的，遗传和功能的基因 参与的证据。其次，我们将分析四个微管基因变化的下游效应， 包括调节元件、转录组其余部分和SZ相关基因的变化， 途径（项目2和核心B）。最后，我们将实施我们的体内测定来解释测序， 候选SZ基因的数据，以建立候选致病等位基因的作用方向， 测量这些位点对SZ的总体负担。总之，我们的工作，在交叉与研究， 中心的其他组成部分，将告知遗传贡献和微管的生物学机制， （dys）功能的SZ病理学的离散方面，并可能有助于改善治疗的设计 范例和未来的临床试验。

Large-scale population genetic studies have begun to map the genetic architecture of schizophrenia (SZ). We now know that the genetic contribution of this multifactorial trait arises from a variety of lesions that include a) rare copy number variants (CNVs) of strong effect; b) common non-coding alleles of mild effect; and c) rare coding alleles that cluster in biological modules. Our recent studies have afforded us the opportunity to synthesize genetic, genomic, and functional studies to dissect the contribution of microtubule and ciliary dysfunction to SZ and to develop physiologically relevant assays to interrogate the effect of genes and alleles as a means of augmenting statistical power. Here, we will continue to focus on a specific biological module, the protein cluster that regulates microtubule function as it relates to axon/dendritic growth and ciliary function, and to dissect its contribution to SZ in terms of CNV pathomechanism; regulatory mutations; and rare alleles of large effect. We are uniquely placed to measure the contribution of this module to SZ. First, we will improve our understanding of the 16p11.2 CNV pathology, one of the most significant contributors to SZ; drawing from expertise both from our group as well as from Projects 2, 3 and Core C, we will test the contributory hypothesis for KCTD13, a gene for which we and others have amassed strong, but indirect, genetic and functional evidence of involvement. Second, we will assay the downstream effect of changes in four microtubule genes, including changes of regulatory elements, on the rest of the transcriptome and on SZ associated genes and pathways (with Project 2 and Core B). Finally, we will implement our in vivo assays to interpret sequencing data on candidate SZ genes in order to establish the direction of effect of candidate pathogenic alleles and to measure the overall burden of these loci to SZ. Taken together, our work, upon intersection with the studies of the other Center components, will inform the genetic contribution and the biological mechanisms of microtubule (dys)function to discrete aspects of SZ pathology and potentially help improve the design of treatment paradigms and future clinical trials.