Genomewide Copy Number Variation Analysis and Association with Facial Shape Variation

全基因组拷贝数变异分析及其与面部形状变异的关联

• 批准号: 8958556
• 负责人: TAMIM H SHAIKH
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958556
• 关键词: 22q11 Deletion Syndrome; Accounting; Affect; African; Algorithms; Anatomy; Appearance; Autistic Disorder; Biological; Caucasians; Characteristics; Child; Congenital Abnormality; Copy Number Polymorphism; Craniofacial Abnormalities; Data; Data Analyses; Data Set; Databases; Dental; Detection; Development; Disease; Ensure; European; Exhibits; Face; Family; Family member; Frequencies; Funding; Funding Opportunities; Gene Dosage; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Goals; Hereditary Disease; Human; Human body; Individual; Measurement; Mediating; Mendelian disorder; Methodology; Morphogenesis; Multiple Birth Offspring; National Institute of Dental and Craniofacial Research; Overlapping Genes; Parents; Pathway interactions; Phenotype; Play; Process; Research Project Grants; Risk; Role; Scanning; Schizophrenia; Shapes; Side; Single Nucleotide Polymorphism; Source; Statistical Data Interpretation; Study Subject; Tanzania; Testing; Variant; Williams Syndrome; base; cohort; craniofacial; developmental genetics; dosage; genetic variant; genome wide association study; genome-wide; offspring; orofacial cleft; public health relevance; rare variant; response; trait

 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.

 描述（由申请人提供）：以家庭为基础的研究表明，遗传因素在面部形状和外观中起着重要作用。然而，人们对正常面部发育和个体间差异的基因知之甚少。在两项正在进行的研究中，以确定面部形状变化的遗传决定因素，3700名非洲班图人和3200名欧洲高加索人（EUR）使用3D形态测量相机拍摄照片，以获得数字化面部扫描，并使用高含量基因分型微阵列进行基因分型。从3D面部扫描获得的精确面部测量结果允许提取定量面部距离和形状，这些距离和形状占研究受试者之间面部形状差异的大部分。目前正在进行这些非洲和欧洲队列中单核苷酸多态性（SNP）与定量面部测量的全基因组关联。除了SNP之外，拷贝数变异（CNVs）现在被认为是人类变异和疾病的遗传变异的重要来源。最近的研究表明，CNVs与几种常见疾病的风险增加有关，最明显的是神经发育疾病，如自闭症和精神分裂症。此外，CNV还直接参与了几种遗传疾病，如22 q11缺失综合征和Williams-Beuren综合征，其中受影响的个体具有特征性的面部畸形。我们推测，正常面部形状和外观的一些变异性是由遗传变异引起的，遗传变异是由影响面部发育基因剂量的拷贝数变异介导的。为了验证我们的假设，我们将首先使用来自用于对班图非洲人和欧元队列进行基因分型的SNP微阵列的现有数据进行CNV分析。然后，我们将以多步骤方法对检测到的CNV与定量面部测量进行关联分析，该方法将测试常见和罕见变体的关联。所提出的分析将直接评估CNVs在面部形状和外观遗传学中的贡献。此外，这些CNVs影响的特定基因的鉴定将大大扩展我们对正常面部形态发生以及颅面异常的遗传和发育途径的理解。