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Mapping Epistatic Modifiers of Human Psychiatric Risk Using Mouse Genetics

利用小鼠遗传学绘制人类精神风险的上位修饰因子

基本信息

批准号：
9196576
负责人：
LAURA J. SITTIG
金额：
$ 1.93万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9196576
关键词：
Mapping Epistatic Modifiers Human Psychiatric

项目摘要

DESCRIPTION (provided by applicant): Bipolar disorder and schizophrenia are highly heritable disorders that are likely due to the actions of a large number of genes. Genome-wide association studies (GWAS) in humans have identified some key candidate genes, but together they explain only a fraction of the heritability. One of the strongest and best replicated candidat genes is CACNA1C, which has been shown to significantly contribute to disease risk for bipolar disorder, schizophrenia, and major depression. Genetic interactions are important in determining a number of traits in model organisms, and may also account for missing heritability in human psychiatric disease. Despite this promise, little progress has been made in understanding epistasis due to the statistical burden of testing for all pairwise interactions across the genome. The key long-term goal of this project is to use mouse genetics to identify epistatic modifier genes that influence risk for psychiatric disease in humans. We will use the Cacna1c+/- (heterozygous knockout) mouse, which exhibits key phenotypes involved in several psychiatric diseases. We will create a panel of isogenic F1 (first filial generation) offspring tha express the Cacna1c+/- allele on a variety of inbred backgrounds. As the phenotypic effects of transgenes are well known to differ across genetic backgrounds, we will take advantage of the phenotypic differences in Cacna1c+/- mice of different backgrounds to map the genetic variants that underlie them. All F1s will be isogenic for half their genome on which they inherit the Cacna1c +/- or +/+ allele on a B6 background; the other half will be of a variable inbred strain. I Specific Aim 1 we will generate this panel of F1 offspring harboring the Cacna1c mutant or wild-type allele on a variety of inbred backgrounds. We will phenotype the panel of F1 mice on a battery of behavioral tests that model specific aspects of neuropsychiatric disease relevant to bipolar disorder and schizophrenia and are already known to be altered in Cacna1c+/- mice. In Specific Aim 2 we will use this phenotypic data to conduct a GWAS using a statistical model that we developed for this study. Aside from genotype at the Cacna1c allele, genotype data for each F1 will be available from public databases. Our GWAS analysis will reveal markers that are associated with the phenotypic traits themselves, similar to results of a conventional GWAS study, as well as markers that modify the susceptibility or resilience to the effect of Cacna1c observed in some but not other F1s. We will then prioritize and narrow down candidate loci using bioinformatics resources; validate candidates using gene expression assays from brains of F1 mice; and conduct final validation by testing in human genetic datasets to which we will have access by collaboration. This is the first large-scale, efficient approach to mapping modifier loci. Findings of this work will be translated directly to human datasets where they may prove to explain individual risk to psychiatric disorder and generate new biological insights and treatment options for psychiatric disease.

描述（由申请人提供）：双相情感障碍和精神分裂症是高度遗传性疾病，可能是由于大量基因的作用。人类全基因组关联研究（GWAS）已经确定了一些关键的候选基因，但它们只能解释一小部分遗传性。最强和最佳复制的候选基因之一是CACNA 1C，它已被证明是双相情感障碍，精神分裂症和重度抑郁症的疾病风险的显着贡献。遗传相互作用在确定模式生物中的许多性状中是重要的，并且也可以解释人类精神疾病中缺失的遗传性。尽管有这样的希望，但由于测试基因组中所有成对相互作用的统计负担，在理解上位性方面几乎没有取得进展。该项目的关键长期目标是利用小鼠遗传学来识别影响人类精神疾病风险的上位修饰基因。我们将使用Cacna 1c +/-（杂合敲除）小鼠，它表现出参与几种精神疾病的关键表型。我们将创建一组在各种近交背景下表达Cacna 1c +/-等位基因的同基因F1（第一代子代）后代。众所周知，转基因的表型效应在不同的遗传背景下是不同的，我们将利用不同背景的Cacna 1c +/-小鼠的表型差异来绘制它们背后的遗传变异。所有的F1将是同基因的一半，他们继承的基因组上的Cacna 1c +/-或+/+等位基因的B6背景;另一半将是一个可变的近交系。I具体目标1我们将在各种近交背景下产生这组携带Cacna 1c突变体或野生型等位基因的F1后代。我们将在一系列行为测试中对F1小鼠进行表型分析，这些行为测试模拟了与双相情感障碍和精神分裂症相关的神经精神疾病的特定方面，并且已知在Cacna 1c +/-小鼠中发生了改变。在具体目标2中，我们将使用我们为此研究开发的统计模型，使用该表型数据进行GWAS。除了Cacna 1c等位基因的基因型外，每个F1的基因型数据将可从公共数据库获得。我们的GWAS分析将揭示与表型性状本身相关的标记，类似于传统GWAS研究的结果，以及改变某些F1中观察到的Cacna 1c效应的易感性或弹性的标记。然后，我们将使用生物信息学资源优先考虑和缩小候选基因座;使用F1小鼠大脑的基因表达测定验证候选基因座;并通过在我们将通过合作访问的人类遗传数据集中进行测试进行最终验证。这是第一个大规模、高效的映射修改器方法的位点这项工作的结果将直接转化为人类数据集，在那里它们可能被证明可以解释精神疾病的个体风险，并为精神疾病产生新的生物学见解和治疗方案。