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

描述(申请人提供)：尽管许多全基因组关联研究(GWAS)试图确定与疾病相关的遗传变异，但所有这些研究都认为两个亲本等位基因具有相同的影响。因此，他们严重缺乏检测印记等影响的能力，这些影响可能会在母亲和父亲的等位基因之间产生差异。我们开发了新的SNP关联方法，利用母亲/父亲/孩子三元组，允许在数量性状和疾病关联研究中检测起源父母的偏差。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，能够检测到使用传统的GWAS方法遗漏的疾病易感基因。通过这种方式，可以检测到在母亲和父亲之间可能起不同作用的印记和其他影响(例如，母亲/胎儿的相互作用)。在我们的初步数据中，我们展示了这种方法在口腔裂隙中检测显示POFO效应的新基因的能力。我们现在建议应用这一方法来详细地重新分析几个大型GWAS数据集，这些数据集的SNP数据来自完整的TRIO，可以通过基因型式和表型数据库(DBGaP)获得。这些研究可能会揭示口腔唇腭裂(OCL/P)、注意力缺陷多动障碍(ADHD)和多发性硬化症(MS)的POFO新效应。这一提议将为印记的影响提供新的见解 以及几种人类疾病中的母婴相互作用。

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.