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

项目概要/摘要 全基因组关联研究 (GWAS) 涉及扫描整个基因组的密集基因型标记，以 发现与特定表型相关的遗传变异。虽然它们更常用于 病例/对照设计来寻找与疾病相关的变异，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 造成多个不同人群的正常面部变化。对于像这样的复杂特征 就面部形状而言，这些研究的结果有些平淡。每项研究似乎都表明 独特的基因组，并且只有 PAX3 在多项研究中得到了复制。一些差异可能是 由于表型量化方式和采用的统计分析方式存在差异。可能更多 令人担忧的是这些研究中所测量的内容缺乏组织特异性。传统套装 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 因其可重复性和易于捕获而被选中，本质上它们位于将受到影响的区域 肌肉张力和神经支配、脂肪量、年龄和面部表情，所有这些都对 与它们相关的环境噪音。毫无疑问，脸型在很大程度上是决定性的 从遗传学上来说，目前在人类面部 GWAS 中测量的表型中信号可能会丢失。在这里我们 提议评估潜在的未开发资源，即多种近交系小鼠，以进行 颅面形状的定量 GWAS。近交系的表型稳定且可重复， 遗传上一致，因此它们的基因型是公开的，无需昂贵的 单独进行基因分型。年龄和其他环境因素对表型的影响也 在近交模型中最小化。我们的 32 个近交系和 10 个 F1 杂交的试点显示出多个基因座 (14) 超过标准单变量映射的显着性阈值。根据试点结果，我们 请求资金使用所有市售近交系进行更广泛的关联研究 具有密集基因分型和多变量关联图谱。对模型生物体进行 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参与程度 表型中的候选基因。小鼠和人类 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有可能 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.