Genome-wide analyses of parent of origin effects in three human disea

三种人类疾病的起源亲本效应的全基因组分析

• 批准号: 8512208
• 负责人: Andrew James Sharp
• 金额: $ 8.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512208
• 关键词: Address; Affect; Alleles; Attention deficit hyperactivity disorder; Autistic Disorder; Child; Collaborations; Complex; Data; Data Set; Detection; Disease; Disease Association; Disease susceptibility; Fathers; Framingham Heart Study; Genes; Genome; Genotype; Heritability; Heterozygote; Human; Inheritance Patterns; Inherited; Metabolism; Methodology; Methods; Mothers; Multiple Sclerosis; Odds Ratio; Parents; Phenotype; Pilot Projects; Predisposition; Premature Birth; Publishing; Relative (related person); Sampling; Susceptibility Gene; Testing; cleft lip and palate; database of Genotypes and Phenotypes; density; disorder risk; fetal; genetic variant; genome wide association study; genome-wide; human disease; imprint; insight; maternal imprint; novel; novel strategies; offspring; oral cleft; public health relevance; trait; transmission process

DESCRIPTION (provided by applicant): Although many genome-wide association studies (GWAS) have sought to identify genetic variants that are associated with disease, all such studies consider the two parental alleles as having identical effects. As a result, they are severely underpowered to detect effects such as imprinting that can operate differentially between the maternal and paternal alleles. We have developed novel SNP association methodologies that utilize mother/father/child trios, allowing the detection of parent of origin biases in both quantitative traits and disease association studies. We show that the use of these novel strategies that analyze disease associations separately for the maternal and paternal alleles are able to detect disease susceptibility genes that are missed using conventional GWAS approaches. In this way imprinting and other effects that can operate differentially between mother and father (e.g. maternal/fetal interactions) can be detected. In our preliminary data, we demonstrate the power of this approach to detect novel genes showing PofO effects in oral clefts. We now propose to apply this methodology to reanalyze in detail several large GWAS datasets for which SNP data from complete trios are available through The Database of Genotypes and Phenotypes (dbGAP). These studies will likely reveal novel PofO effects operating in Oral Cleft Lip/Palate (OCL/P), Attention Deficit Hyperactivity Disorder (ADHD) and Multiple Sclerosis (MS). This proposal will provide novel insights into the influence of imprinting and maternal/fetal interactions in several human diseases.

描述（由申请人提供）：尽管许多全基因组关联研究（GWAS）试图鉴定与疾病相关的遗传变异，但所有此类研究均认为两个亲本等位基因具有相同的效应。因此，它们的检测能力严重不足，无法检测到诸如印记等效应，这些效应可以在母本和父本等位基因之间产生差异。我们已经开发了新的SNP关联方法，利用母亲/父亲/孩子三重奏，允许检测数量性状和疾病关联研究中的起源偏差的父母。我们表明，使用这些新的策略，分别分析母亲和父亲的等位基因的疾病关联能够检测疾病易感基因，错过了使用传统的GWAS方法。以这种方式，可以检测可以在母亲和父亲之间差异地操作的印记和其他效应（例如，母亲/胎儿相互作用）。在我们的初步数据中，我们证明了这种方法检测新基因的能力，这些新基因在口裂中显示出PofO效应。我们现在建议应用这种方法来重新详细分析几个大型GWAS数据集，这些数据集的SNP数据可以通过基因型和表型数据库（dbGAP）获得。这些研究可能会揭示在口腔唇腭裂（OCL/P），注意力缺陷多动障碍（ADHD）和多发性硬化症（MS）中起作用的新型PofO效应。这一建议将提供新的见解印迹的影响 和母体/胎儿的相互作用。