The Genetic Architecture of Human Facial Morphology

大量证据表明，面部形态有很强的遗传基础。然而，相对较少的是 知道特定的基因变异如何影响人类面部特征的大小和形状。更深一层的 对这些性状的遗传基础的了解可能有助于深入了解 颅面形态发生，提高了我们对基因和基因之间复杂关系的认识 头面部综合征和出生缺陷的表型，并最终为预测面部 颅面外科和正畸治疗计划的特点。该项目有两个主要目标：(1) 绘制影响正常人类面部形态的遗传变异图；以及(2)确定这些变异是否 在非综合征性口腔裂伤中起一定作用。为了实现第一个目标，我们将生成量化的面部 将一种新的形态测量方法应用于具有可用3D面部的现有数据集的形状表型 图像和全基因组标记(n=10,482)。这一新的表型方法，在多变量GWAs中 框架，将使我们能够在多个组织水平上模拟遗传对面部形态的影响-来自 高度本地化到更全球化的面部区域。我们将通过研究 这些变体在脑神经脊细胞调节中的作用。最后，通过描述关系和 相关变异之间的相互作用，我们将更好地理解 人类面部变异。为了实现第二个目标，我们将评估基因变异是否与 在我们正常的面部队列中，面部形状的特定方面也有助于遗传病因 非综合征性口面部裂，人类最常见的颅面畸形。塑造我们的方面 将重点放在根据先前的证据确定某些面部特征是口腔面部的易感因素 裂隙(例如，患有裂隙儿童的未受影响的父母的面部中部宽度增加)。我们将测试这些 在现有的非综合征性唇裂病例的多民族队列中，与口面部裂伤相关的变异 其未受影响的一级亲属(n=9213)。然后我们将确定这些变种的程度 修改并与先前发现的裂位基因相互作用，以影响表型严重程度。通过利用大型 现有数据资源的数量和在3D表型-基因型建模方面的最新进展， 目前的方案是迄今为止绘制人类面部基因座图最全面的努力。 先天畸形的变异和获得对遗传病因的重要见解的机会 这对全世界的人类都有影响。

Numerous lines of evidence indicate facial morphology has a strong genetic basis. However, relatively little is known about how specific genetic variants influence the size and shape of facial features in humans. A deeper understanding of the genetic basis of such traits may provide insights into the fundamental mechanisms of craniofacial morphogenesis, improve our knowledge of the complex relationship between genotype and phenotype in craniofacial syndromes and birth defects, and eventually provide a basis for predicting facial features for treatment planning in craniofacial surgery and orthodontics. This project has two major aims: (1) map genetic variants influencing normal human facial morphology; and (2) determine whether such variants play a role in nonsyndromic orofacial clefting. To accomplish the first aim, we will generate quantitative facial shape phenotypes by applying a novel morphometric approach to existing datasets with available 3D facial images and genome-wide markers (n=10,482). This novel phenotyping approach, within a multivariate GWAS framework, will allow us to model genetic effects on facial morphology at multiple levels of organization – from highly localized to more global facial regions. We will begin to explore putative functionality by investigating the role of these variants in cranial neural crest cell regulation. Finally, by characterizing the relationships and interactions among associated variants, we will gain a better understanding of the genetic architecture of human facial variation. To accomplish the second aim, we will evaluate whether genetic variants associated with specific aspects of facial shape in our normal facial cohorts also contribute to the genetic etiology of nonsyndromic orofacial clefting, the most common craniofacial anomaly in humans. The aspects of shape we will focus on are based on prior evidence identifying certain facial features as predisposing factors to orofacial clefting (e.g., increased midfacial width in the unaffected parents of children with clefts). We will test these variants for association with orofacial clefting in an existing multiethnic cohort of nonsyndromic cleft cases and their unaffected first-degree relatives (n=9213). We will then determine the degree to which such variants modify and interact with previously identified cleft loci to influence phenotypic severity. By leveraging a large number of existing data resources and applying state-of-the-art advances in 3D phenotype-genotype modeling, the current proposal represents the most comprehensive effort to date to map the loci underlying human facial variation and an opportunity to gain important insights into the genetic etiology of a congenital malformation that impacts humans worldwide.