Parent-of-Origin Effects on Food Allergy

描述(申请人提供)：食物过敏(FA)是一种对食物的过敏性反应，在美国和世界范围内是一个日益严重的临床和公共卫生问题。FA是一个复杂的性状，是多种遗传和环境因素及其相互作用的结果。然而，调节个体对FA易感性的特定遗传标记仍有待确定。我们正在芝加哥队列中进行的FA全基因组关联研究是第一个全面识别FA易感变异的研究。与其他遗传算法相似，它将父系和母系遗传等位基因对FA的遗传效应一视同仁，使得FA相关的印记基因不能被识别。此外，还没有研究考察母体对FA的遗传影响。作为一种儿童早期发病的疾病，母体基因可能通过对宫内环境的影响在FA的发生发展中起关键作用。为了补充我们对FA的研究，并寻找缺失的遗传性，这项研究的中心焦点是检查母体和印记效应 关于FA，两种类型的父母起源效应(POE)，通过利用芝加哥队列中在851个FA家庭中产生的现有Gwas数据。具体地说，我们建议实现两个主要目标。目的：我们将使用对数线性似然比检验(LL-LRT)在631个高加索家庭(约占FA总样本的80%)中检测母亲对FA的遗传效应，该检验能够通过子代、母亲和两者来检验遗传效应。我们还将对母体遗传对FA的影响进行通径分析。AIM2：我们将测试印记效应，这代表了FA病例通过母系遗传的相对风险- 在631个使用LL-LRT的高加索人FA家系中，在调整了母体基因的混杂效应后，传递的等位基因与FA病例遗传父系传递的等位基因的风险。这项研究将是第一次大规模的全基因组POE对FA的研究。这代表着在补充我们对FA遗传基础的理解方面向前迈出了重要的一步。这些发现可以部分解释关于FA遗传易感性的基因组缺失的遗传性。我们期望这项研究可以改变我们对FA的理解，并导致FA新的遗传机制的确定，这将有助于我们开发一个有希望的范例来识别FA的高危个体，并最终设计有效的FA预防和治疗策略。

DESCRIPTION (provided by applicant): Food allergy (FA), a hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. and worldwide. FA is a complex trait, as a result of multiple genetic and environmental factors and their interactions. However, specific genetic markers that can modulate individual susceptibility to FA remain to be determined. Our ongoing genome-wide association study (GWAS) of FA in the Chicago Cohort is the first study to comprehensively identify susceptibility variants for FA. Similar to other GWAS, it treats the genetic effects from the paternally- and maternally-transmitted allele on FA equally, such that FA-associated imprinted genes could not be identified. Moreover, no study has examined maternally-mediated genetic effects on FA. As an early childhood onset disease, maternal genotypes may play crucial roles in the development of FA, possibly through their influence on the intrauterine environment. To complement our GWAS of FA and search for the missing heritability, the central focus of this study is to examine maternal and imprinting effects on FA, two types of parent-of-origin effects (POE), by leveraging the existing GWAS data generated in 851 FA families from the Chicago Cohort. Specifically, we propose to accomplish two primary aims. Aim1: we will test maternally-mediated genetic effects on FA in 631 Caucasian families (~80% of the samples from the GWAS of FA) using log-linear likelihood ratio tests (LL-LRT), which are able to examine genetic effects through the offspring, mother, and both. We also will conduct pathway analysis of maternal genetic effects on FA. Aim2: We will test for imprinting effects, which represent the relative risk of FA cases inheriting a maternally- transmitted allele vs. the risk of FA cases inheriting a paternally-transmitted allele, in 631 Caucasian FA families using LL-LRT after the adjustment of confounding effects from maternal genotypes. This study will be the first large-scale genome-wide study of POE on FA. This represents a significant step forward in complementing our understanding of the genetic basis of FA. The findings could partially explain the missing heritability of the genome regarding the genetic susceptibility of FA. We anticipate that this study may transform our understanding of FA and lead to the identification of novel genetic mechanisms of FA, which will help us to develop a promising paradigm for identifying individuals at high risk for FA, and ultimately design effective strategies for the prevention and treatment of FA.