Inbred Mice Strains: Untapped Resource For Genome-Wide Quantitative Association Study For Craniofacial Shape

项目总结/摘要 全基因组关联研究（GWAS）涉及在基因组中扫描密集的基因型标记， 发现与特定表型相关的遗传变异。虽然它们更常用于 为了找到与疾病相关的变异，表型可以是定量的，并且可以 用于了解遗传基础表型变异。现在有五个GWAS试图寻找基因 负责多个不同人群的正常面部变化。对于一个复杂的特征， 面部形状，这些研究的结果有些平淡无奇。每项研究似乎都表明 独特的基因组，只有PAX 3在多项研究中得到了复制。其中一些差异可能是 这是由于表型如何定量和所采用的统计分析的差异。可能更 令人担忧的是，在这些研究中，缺乏确切测量的组织特异性。传统布景 人脸上的解剖标志集中在眼睛、鼻子和嘴巴周围。虽然这些地标是 选择它们是因为它们的可重复性和易于捕获，从本质上讲，它们位于将受到以下因素影响的地区： 肌肉张力和神经支配，脂肪量，年龄和面部表情，所有这些都具有实质性的 与之相关的环境噪音。毫无疑问，面部形状在很大程度上取决于 在遗传学上，该信号可能在人类面部GWAS的当前测量表型中丢失。这里我们 建议评估一个潜在的未开发的资源，不同的近交系小鼠，进行 颅面形态的定量GWAS。近交系中的表型是稳定的和可重复的， 遗传上是统一的，因此它们的基因型是公开的，不需要昂贵的 基因分型年龄和其他环境因素对表型的影响也是 最小化的近亲繁殖模型。我们的试验用32个自交系和10个F1杂交组合显示多个位点（14）。 超过标准单变量映射的显著性阈值。根据试点的结果，我们 申请资金，使用所有商业上可获得的近交系进行更广泛的关联研究 密集基因分型和多变量关联作图。在模式生物上做GWAS仍然是 与人类研究相关，其中大多数转向小鼠模型，以进一步评估其 表型中的候选基因。小鼠和人GWA之间的任何重叠发现都将证实 该基因座对人类表型的贡献。新基因变异的鉴定也可能 影响未来人类研究的方向。

PROJECT SUMMARY/ABSTRACT Genome-wide association studies (GWAS) involves scanning dense genotype markers across the genomes to find genetic variations associated with a particular phenotype. While they are more commonly used in case/control designs to find variants associated with a disease, the phenotypes can be quantitative, and can be used to understand genetic basis phenotypic variation. There are now five GWAS that tried to find genes responsible for the normal facial variation in multiple different human populations. For a complex trait like a facial shape, findings of these studies have been somewhat underwhelming. Each study appears to identify unique sets of genes, and only PAX3 has been replicated in multiple studies. Some of the differences might be due to differences in how phenotypes were quantified and the statistical analysis employed. Potentially more concerning is the lack of tissue specificity of what is exactly being measured in these studies. Traditional sets of anatomical landmarks on human face cluster around eyes, nose, and mouth. While these landmarks are selected for their repeatability and ease of capture, by nature they are on regions that will be impacted by muscle tone and innervation, amount of fat, age, and facial expression, all of which has substantial environmental noise associated with them. While there is no question facial shape is largely determined genetically, the signal may be lost in the current measured phenotype in human facial GWAS. Here we propose to evaluate a potentially untapped resource, diverse set of inbred strains of mice, to conduct quantitative GWAS for craniofacial shape. Phenotypes in inbred strains are stable and reproducible, they are genetically uniform and as such their genotypes are publicly available, negating the need for expensive genotyping individually. The impact of age and other environmental factors on the phenotype are also minimized in inbred models. Our pilot with 32 inbred strains and 10 F1 crosses showed multiple loci (14) exceeding the significance threshold with standard univariate mapping. Based on the results of the pilot we request funds to conduct a more extensive association study using all commercially available inbred strains with dense genotyping and multivariate association mapping. Doing a GWAS on a model organism is still relevant to the human studies, most of which turn to mouse models to further evaluate the involvement of their candidate genes in the phenotype. Any overlapping finding between mouse and human GWA will confirm the contribution of that locus to the phenotype in humans. Identification of novel gene variants can also potentially influence the direction of the future studies in humans.