Parent-of-Origin Effects on Food Allergy

描述（由申请人提供）：食物过敏（FA）是对食物的超敏反应，在美国和全球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，具体的遗传标记，可以调节个人的易感性FA仍有待确定。我们正在进行的芝加哥队列FA全基因组关联研究（GWAS）是第一项全面识别FA易感性变异的研究。与其他GWAS相似，它同等对待来自父传和母传等位基因对FA的遗传效应，使得FA相关的印迹基因不能被识别。此外，还没有研究探讨母源性遗传对FA的影响。作为一种儿童早期发病的疾病，母亲的基因型可能在FA的发展中起着至关重要的作用，可能是通过他们对宫内环境的影响。为了补充我们对FA的GWAS和寻找缺失的遗传力，本研究的中心焦点是检查母体和印迹效应 在FA，两种类型的父母的原产地的影响（POE），利用现有的GWAS数据产生的851个FA家庭从芝加哥队列。具体而言，我们建议实现两个主要目标。目标1：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80%的来自FA的GWAS样本）中测试母体介导的遗传效应对FA的影响，该检验能够通过后代、母亲以及两者来检查遗传效应。我们还将进行母体遗传对FA影响的通径分析。目标2：我们将测试印记效应，这代表了FA病例遗传母系- 在调整了来自母亲基因型的混杂效应后，在631个使用LL-LRT的高加索FA家族中，使用LL-LRT比较了遗传等位基因的FA病例与遗传父源遗传等位基因的FA病例的风险。这项研究将是第一个大规模的全基因组研究的POE对FA。这代表着我们在补充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FA遗传易感性基因组遗传力缺失的原因。我们预计，这项研究可能会改变我们对FA的理解，并导致识别FA的新的遗传机制，这将有助于我们开发一个有前途的范式，用于识别FA的高风险个体，并最终设计预防和治疗FA的有效策略。

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.