Project 1

大规模的人群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 现在我们知道，这种多因素特征的遗传贡献来自于各种病变，包括) 效应较强的罕见拷贝数变异(CNV)；b)效应较弱的常见非编码等位基因；以及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、基因组和功能研究来剖析微管和纤毛的作用 对SZ的功能障碍和开发生理相关的测试以询问基因和等位基因的影响 作为增强统计权力的一种手段。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，因为它与轴突/树突状细胞生长和睫毛功能有关 从CNV致病机制、调节性突变和罕见的等位基因等方面剖析其对SZ的贡献 影响很大。我们在衡量这一模块对深圳的贡献方面处于独特的地位。首先，我们将提高我们的 对16p11.2 CNV病理的理解，这是SZ最重要的贡献之一； 来自我们小组以及项目2、3和核心C的专业知识，我们将检验贡献性假设 对于KCTD13，我们和其他人积累了强大的、间接的、遗传的和有功能的基因 牵涉其中的证据。第二，我们将分析四个微管基因的变化对下游的影响， 包括调控元件、转录组其余部分和SZ相关基因的变化 路径(包括项目2和核心B)。最后，我们将实施体内分析来解释测序 关于候选SZ基因的数据，以确定候选致病等位基因的作用方向，并 测量这些基因座对深圳的总体负担。综上所述，我们的工作与 其他中心成分将告知微管的遗传贡献和生物学机制 (DYS)对SZ病理的离散方面的作用，并可能有助于改进治疗设计 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.