Methods, software, and analyses of genomic data in multiplex oral cleft families

多重口裂家族基因组数据的方法、软件和分析

• 批准号: 8952405
• 负责人: Ingo Ruczinski
• 金额: $ 28.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952405
• 关键词: ADAMTS9 gene; Affect; Alleles; Birth; CDH1 gene; Candidate Disease Gene; Cleaved cell; Complex; Computer software; Copy Number Polymorphism; Craniofacial Abnormalities; DNA copy number; Data; Data Analyses; Disease; Documentation; Event; Extended Family; Family; Family Study; Family member; Genetic; Genetic Heterogeneity; Genome; Genomics; Goals; Heritability; Individual; Methodology; Methods; Nuclear Family; Nucleotides; Penetrance; Population; Prevalence; Probability; Publishing; Race; Rare Diseases; Relative (related person); Research; Risk; Sample Size; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Site; Sum; Variant; base; design; disorder risk; exome; exome sequencing; genetic pedigree; genetic variant; genome-wide; member; method development; next generation sequencing; novel; open source; oral cleft; population based; proband; public health relevance; rare variant; risk variant; software development; trait

 DESCRIPTION (provided by applicant): Considerable genetic heterogeneity must be expected with any complex disease such as oral clefts, where rare variants could explain part of the so-called "missing heritability". In extended families with multiple affected members, there is a high probability that several of these affected relatives carry the same rare, high penetrance risk variant if such a variant is found in one affected individual. We recently developed a general framework for calculating rare nucleotide variant sharing probabilities when two or more affected subjects from an extended family are sequenced, and show how information from multiple families can be combined by calculating a p-value as the sum of the probabilities of sharing events equal or more extreme. We also examined the impact of unknown relationships (i.e. cryptic relatedness), and proposed methods to approximate sharing probabilities based on empirical estimates of kinship between family members obtained from genome-wide marker data. We applied this method to the whole exome sequence data in a study of 55 multiplex cleft families with apparent non-syndromic forms of oral clefts from four distinct populations, and identified a genome-wide significant rare variant in the gene ADAMTS9 shared by affected relatives in three Indian families. An additional, more targeted analysis focused on 348 oral cleft candidate genes identified an additional potentially damaging SNV in CDH1 in a single family. In this application, we propose to extend this approach to rare DNA copy number variants, to implement an open source software package for genomic array and sequencing data, scalable and suitable for reproducible genomic research, and to use existing oral cleft data to identify novel and rare high penetrance genetic variants underlying oral cleft risk.

 描述（由适用提供）：在任何复杂的疾病（例如口服裂缝）中，必须期望相当大的遗传异质性，在这种疾病中，罕见的变体可以解释所谓的“缺乏遗传力”的一部分。在有多个受影响成员的大家庭中， 如果在一个受影响的个体中发现这样的变体，则这些受影响的亲戚中有几个具有相同罕见的高渗透风险变体的可能性很高。我们最近开发了一个将军 测序两个或多个受影响的受试者时，用于计算稀有核苷酸变体共享可能性的框架，并通过计算p值将共享事件的可能性相等或更极端来显示如何通过计算p值来结合来自多个家族的信息。我们还研究了未知关系（即加密相关性）的影响，并提出了基于从全基因组标记数据获得的家庭成员之间亲属关系的经验估计来近似共享可能性的方法。我们将这种方法应用于整个外显子组序列数据中，研究了55个多重裂口家族，这些家族具有来自四个不同种群的明显非综合性形式的口腔裂口，并确定了三个印度家庭中受影响的亲戚共享的基因组范围的明显稀有变体。另一个更具针对性的分析，重点是348口腔裂。 候选基因在单个家族中发现了CDH1中额外的潜在损害SNV。在此应用程序中，我们建议将这种方法扩展到稀有的DNA拷贝数变体，以实现用于基因组阵列和测序数据的开源软件包，可扩展且适合于可重复的基因组研究，并使用现有的口腔裂口数据来识别新型和稀有的高渗透性遗传遗传变异的口腔left裂风险。