The Genetic Landscape of Human Tooth Agensis

人类牙齿发育的遗传图谱

• 批准号: 10748099
• 负责人: Jennifer Below
• 金额: $ 27.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2023-08-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10748099
• 关键词: Genetic; Landscape; Human; Tooth; Agensis

PROJECT SUMMARY The goal of this project is to discover candidate causal genetic variants for human tooth agenesis (TA), a common craniofacial birth defect that affects ~200 million humans worldwide and imposes significant esthetic, functional, psychosocial, and financial burdens for affected individuals. Despite research progress, mutations in known TA genes account for less than 50% of all cases, suggesting that additional causal genes remain to be found. Genome-wide studies of TA are scarce and, in addition, interpretation of identified variants has been challenging due to the paucity of studies combining gene discovery with functional genomic approaches. This complicates our understanding of TA genotype-phenotype correlations and further limits our ability to improve diagnostic and tooth replacement therapies. In this proposal, we will identify and functionally characterize the underlying genetic variations in familial and sporadic TA to improve our understanding of the biological pathways involved in the condition. To achieve our goal, we will: (1) perform whole exome sequencing (WES) of 450 individuals from our well-characterized TA families and case-control cohort, and apply robust bioinformatic analysis integrating publicly available data to identify putative causal variants, (2) characterize prioritized variants using functional genomic approaches in vitro, and (3) apply a PheWAS approach (phenome-wide association study) to determine the broader clinical significance of TA genes by linking TA genetic variants with additional health outcomes captured through a large DNA databank (BioVu Biobank). This study combines genome-wide discovery with biological experimentation, and leverages existing resources (DNA samples, genetic and phenotypic data from BioVu, established in vitro model) within a multi-pronged framework to identify novel TA genes/pathways. Therefore, this study is not only innovative in its approach, but in its capacity to overcome the limitations of traditional TA candidate gene studies. We have exciting published and unpublished data in support of these proposed studies that will greatly enhance our understanding of the molecular mechanisms underlying TA and provide the scientific basis for the development of patient-centered diagnostic and future translational research on tooth replacement therapies. Finally, this study directly addresses the NIDCR's notice of special interest in “Supporting Discovery Of Genetic Variants Underlying Dental, Oral and Craniofacial Diseases and Conditions”.

项目概要 该项目的目标是发现人类牙齿发育不全 (TA) 的候选因果遗传变异，这是一种常见的牙齿发育不全 (TA) 疾病。 颅面部先天缺陷影响着全世界约 2 亿人，对美观、功能、 尽管研究取得了进展，但已知的 TA 发生了突变。 基因占所有病例的比例不到 50%，这表明还有其他致病基因有待发现。 TA 的全基因组研究很少，此外，对已识别变异的解释也具有挑战性 由于缺乏将基因发现与功能基因组方法相结合的研究。 我们对 TA 基因型-表型相关性的理解进一步限制了我们改进诊断和治疗的能力 在本提案中，我们将识别潜在的遗传因素并对其进行功能表征。 家族性和散发性 TA 的变异，以提高我们对涉及 TA 的生物学途径的理解 为了实现我们的目标，我们将：(1) 对我们的 450 名个体进行全外显子组测序 (WES)。 充分表征 TA 家族和病例对照队列，并应用稳健的生物信息分析整合 公开可用的数据来识别假定的因果变异，（2）使用函数来表征优先变异 体外基因组方法，以及 (3) 应用 PheWAS 方法（表组范围关联研究）来确定 通过将 TA 基因变异与其他健康结果联系起来，了解 TA 基因更广泛的临床意义 该研究将全基因组发现与大型 DNA 数据库 (BioVu Biobank) 结合起来。 生物实验，并利用现有资源（DNA 样本、遗传和表型数据） BioVu，建立的体外模型）在多管齐下的框架内识别新的 TA 基因/途径。 因此，本研究不仅在方法上具有创新性，而且在克服现有技术局限性方面也具有创新性。 我们有令人兴奋的已发表和未发表的数据来支持这些研究。 提出的研究将极大地增强我们对 TA 和分子机制的理解 为以患者为中心的诊断和未来转化研究的发展提供科学依据 最后，这项研究直接解决了 NIDCR 特别关注的问题。 “支持发现牙科、口腔和颅面疾病和病症的遗传变异”。