Genomewide Copy Number Variation Analysis and Association with Facial Shape Variation

 描述(由申请人提供)：基于家庭的研究表明，遗传因素对面部形状和外表起着重要作用。然而，人们对正常面部发育的基础基因以及解释个体间差异的基因知之甚少。在两项正在进行的识别面部形状变异背后的遗传决定因素的研究中，使用3D形态测量相机拍摄了3700名班图非洲人和3200名欧洲裔高加索人(EUR)的照片，以获得数字化的面部扫描，并使用高含量基因分型微阵列进行了基因分型。从3D面部扫描获得的精确面部测量，允许提取定量的面部距离和形状，这是研究对象之间面部形状差异的主要原因。在这些非洲和欧洲队列中，单核苷酸多态(SNPs)与面部定量测量的全基因组关联目前正在进行中。除了SNPs，拷贝数变异(CNV)现在被认为是人类变异和疾病的一个重要的遗传变异来源。最近的研究表明，CNV与几种常见疾病的风险增加有关，最明显的是自闭症和精神分裂症等神经发育疾病。此外，CNV还直接与几种遗传疾病有关，如22q11缺失综合征和Williams-Beuren综合征，在这些疾病中，受影响的个人具有特征性的面部变形。我们假设，正常面部形状和外表的一些变异是由影响面部发育相关基因剂量的拷贝数变异所介导的遗传变异造成的。为了验证我们的假设，我们将首先使用来自SNP微阵列的现有数据进行CNV分析，该微阵列用于对Bantu African和EUR队列进行基因分型。然后，我们将以多步骤的方法对检测到的CNV与定量面部测量进行关联分析，这将测试常见和罕见变异之间的关联。拟议的分析将直接评估CNV在面部形状和外表遗传学中的贡献。此外，识别受这些CNV影响的特定基因将极大地扩大我们对正常面部形态发生和颅面异常背后的遗传和发育途径的理解。

 DESCRIPTION (provided by applicant): Family-based studies have indicated that genetic factors play a significant role in facial shape and appearance. However, very little is known about the genes that underlie normal facial development and account for inter-individual variability. In two ongoing studies to identify the genetic determinants underlying facial shape variation, 3700 Bantu Africans and 3200 European-derived Caucasians (EUR) were photographed using 3D morphometric cameras to obtain digitized facial scans and genotyped using high-content genotyping microarrays. The precise facial measurements obtained from 3D facial scans, allowed the extraction of quantitative facial distances and shapes which account for the majority of facial shape variance among study subjects. Genome-wide association of single nucleotide polymorphisms (SNPs) with the quantitative facial measurements in these African and European cohorts, are currently ongoing. In addition to SNPs, copy number variations (CNVs) are now recognized as a significant source of genetic variation underlying human variability and disease. Recent studies have led to the association of CNVs to increased risk for several of common diseases, most notably neurodevelopmental diseases like autism and schizophrenia. Furthermore, CNVs have been directly implicated in several genetic disorders such as the 22q11 deletion syndrome and Williams-Beuren syndrome, in which the affected individuals have characteristic facial dysmorphia. We hypothesize that some of the variability in normal facial shape and appearance results from genetic variation mediated by the copy number variation affecting the dosage of genes involved in facial development. To test our hypothesis, we will first carry out a CNV analysis using the existing data from the SNP microarrays used to genotype the Bantu African and EUR cohorts. We will then carry out association analysis of the detected CNVs with the quantitative facial measurements in a multistep approach, which will test for the association of both common and rare variants. The proposed analysis will directly assess the contribution of CNVs in the genetics of facial shape and appearance. Furthermore, the identification of specific genes affected by these CNVs will greatly expand our understanding of the genetic and developmental pathways underlying normal facial morphogenesis as well as craniofacial abnormalities.