Analyzing nonsyndromic orofacial clefts GWAS data with case-parent trio design

使用病例亲子三人组设计分析非综合征性口面裂 GWAS 数据

• 批准号: 10436788
• 负责人: Zhongxue Chen
• 金额: --
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436788
• 关键词: Biology; Childhood; Cleft Lip; Cleft Palate; Clinical Research; Communities; Computer software; Congenital Abnormality; Data; Dental; Detection; Development; Developmental Biology; Disease; Early Diagnosis; Failure; Genes; Genetic; Genetic Diseases; Genomics; Genotype; Goals; Heritability; Knowledge; Lead; Meta-Analysis; Methodology; Methods; Mission; National Institute of Dental and Craniofacial Research; Oral; Outcome; Parents; Phenotype; Play; Prevention; Public Health; Publishing; Research; Research Personnel; Role; Signal Transduction; Statistical Methods; Stratification; Techniques; Testing; Time; Translational Research; Variant; Work; base; craniofacial; design; diagnostic value; family genetics; genetic information; genetic risk factor; genetic variant; genome wide association study; human disease; improved; innovation; novel; novel therapeutic intervention; orofacial cleft; targeted treatment; transmission process

PROJECT SUMMARY Case-parent trio (CPT) design is widely used in genome-wide association studies (GWASs) for childhood diseases, including nonsyndromic orofacial cleft birth defects (cleft lip and cleft palate). To detect associated genetic variants, the transmission disequilibrium test (TDT)—which is known to be robust against the subpopulation stratification—is usually applied to CPT data. However, several limitations associated with TDT- based methods may result in serious power loss and failure to detect true signals; this problem shows up in current nonsyndromic orofacial cleft GWASs, as only a small portion of associated genetic variants have been identified so far. Substantially more powerful advanced statistical approaches are therefore desperately needed. We propose some cutting-edge statistical methods that circumvent the limitations of current tests and use extra information from the data to substantially gain detection power. By applying our proposed methodology to nonsyndromic orofacial cleft GWAS data with CPT design, we expect to discover many novel genetic risk factors. The long-term goal of this project is to help researchers better understand the underlying mechanisms of these conditions by using cutting-edge statistical approaches to identify genetic components of nonsyndromic orofacial cleft birth defects, leading to more refined diagnostic capabilities and ultimately better targeted therapies. The overall objective of this application is to develop robust and powerful statistical approaches and apply them to the orofacial cleft birth defects data to discover novel genetic risk factors. The central hypothesis is that powerful statistical approaches can be developed if useful information from the data is obtained and fully and efficiently used; meanwhile, through use of these powerful cutting-edge statistical methods, more disease genetic variants will be discovered. The rationale for the proposed research is that successful completion will enable us to obtain more useful genetic information for nonsyndromic orofacial clefts. The central hypothesis will be tested and the objective attained by pursuing the following specific aims: 1) Develop, test, and validate powerful and robust statistical approaches for nonsyndromic orofacial cleft GWAS with case-parent trio design; 2) Identify novel disease genetic components by applying the proposed powerful statistical approaches to the orofacial cleft birth defects data. The contribution of this project will be significant because the findings will advance knowledge of developmental biology and create new opportunities for clinical and translational research in nonsyndromic orofacial cleft birth defects. This proposed research is innovative because the proposed novel statistical approaches are more powerful than existing methods in that they harness more information from the data and use it more efficiently.

项目摘要 案例 - 父母三重奏（CPT）设计被广泛用于童年的全基因组关联研究（GWASS） 疾病，包括非同伴的口腔裂裂（唇裂和left裂）。检测相关 遗传变异，传输二二曲测试（TDT） - 众所周知 亚种群分层 - 通常应用于CPT数据。但是，与TDT-相关的几个限制 基于基于的方法可能会导致严重的功率损失和无法检测到真正信号的方法；这个问题出现在 当前的非同步口面裂gwass，因为仅相关遗传变异的一小部分 到目前为止确定。因此，绝对需要更强大的高级统计方法。 我们提出了一些尖端的统计方法，以规避当前测试的局限性并使用额外的测试 从数据到实质上获得检测能力的信息。通过将我们建议的方法应用于 我们希望发现许多新型的遗传危险因素的非斑块的口面裂口GWAS数据。 该项目的长期目标是帮助研究人员更好地了解这些项目的潜在机制 通过使用最先进的统计方法来识别非同步Orofacial的遗传成分的条件 裂口出生缺陷，导致更精致的诊断能力，并最终获得更好的靶向疗法。 该应用程序的总体目的是开发强大而有力的统计方法，并将其应用于 口面裂口出生缺陷数据以发现新的遗传危险因素。中心假设是强大的 如果从数据中获得有用的信息，可以完全有效地开发统计方法 用过的;同时，通过使用这些强大的尖端统计方法，更多的疾病遗传变异 将被发现。拟议研究的理由是，成功完成将使我们能够获得 非同步口面裂裂的更有用的遗传信息。中心假设将进行测试，并 通过追求以下特定目的而附加的目标：1）开发，测试和验证强大而健壮的 具有案例三重奏设计的非混合异构裂隙GWA的统计方法； 2）识别小说 疾病遗传成分通过将提议的强大统计方法应用于口面裂。 缺陷数据。该项目的贡献将是重要的，因为这些发现将提高知识 发育生物学并为非伴侣的临床和翻译研究创造新的机会 口面上的先天缺陷。这项拟议的研究具有创新性，因为拟议的新型统计 方法比现有方法更强大，因为它们从数据和 更有效地使用它。