Identifying arsenic susceptibility variants using a functional screening approach

描述(由申请人提供)：确定基因与环境(GxE)的相互作用是寻求了解复杂、多因素疾病易感性的核心挑战。 发展对遗传变异如何改变环境暴露的影响(反之亦然)的理解，将增强我们对疾病机制的知识，并提高我们预测疾病和针对高危亚人群进行干预的能力。不幸的是，在流行病学背景下确定GxE相互作用方面取得的进展有限。大多数全基因组相互作用(GWI)研究仅依靠相互作用的统计证据，往往不足以检测适度的相互作用。在这个提案中，我们描述了一种新的两步“GxE-OMIC”方法，该方法解决了标准GWI方法的局限性。我们将使用孟加拉一项大型队列研究的现有遗传和分子数据来应用我们的方法，该研究专门为评估砷暴露对健康的影响而设计。我们建议通过首先在全基因组范围内搜索SNPs来研究基因-砷的相互作用，该SNPs可以改变砷对分子(组)表型(即，全基因组测量的基因表达和DNA甲基化表型)的影响(目标1)。使用这组与砷相互作用的SNPs来影响分子表型，然后我们将测试SNP-砷的相互作用与砷相关的健康状况：皮肤皮损状况和糖尿病相关表型(目标2)。作为第二个目标，我们将尝试通过对我们选定的临床表型进行常规的GWI分析，利用已建立的利用病例和对照中的基因-环境相关性信息以及边缘基因-疾病关联的信息，识别与砷相互作用影响疾病但未被选入目标1“GxE-OMIC”筛查的SNPs。通过使用高质量的砷暴露测量方法，并将分析限制在与砷相互作用概率更高的SNPs上，我们很有可能克服标准GWI方法的局限性。我们的团队是实现这些目标的理想人选，因为我们对砷暴露对健康的影响和砷毒性的遗传易感性进行了广泛的研究，并在环境流行病学、统计遗传学和分子基因组学方面拥有丰富的经验。我们相信，将GxE研究的重点从不可知的基因组范围的相互作用测试转移到了解基因变异如何在分子水平上影响人类对暴露的反应是很有希望的。我们的方法具有极高的潜力来提高GWI研究的能力，使我们能够识别相互作用，从而增强我们对疾病病因学的理解，以及我们开发针对易感亚群的干预措施的能力。此外，在我们正在进行的纵向研究中，这里描述的方法可能被用来研究GxE与广泛的暴露和疾病结果的相互作用。

DESCRIPTION (provided by applicant): Identifying gene-by-environment (GxE) interactions is a central challenge in the quest to understand susceptibility to complex, multi-factorial diseases. Developing an understanding of how genetic variation alters the effects of environmental exposures (and vice versa) will enhance our knowledge of disease mechanisms and improve our ability to predict disease and target interventions to high-risk sub-populations. Unfortunately limited progress has been made identifying GxE interactions in the epidemiological setting. Most genome-wide interaction (GWI) studies rely on statistical evidence of interaction alone and are often likely to be underpowered to detect modest interactions. In this proposal, we describe a novel two-step "GxE-omic" approach that addresses the limitations of standard GWI approaches. We will apply our approach using existing genetic and molecular data from a large Bangladeshi cohort study specifically designed to assess the effect of arsenic exposure on health. We propose to search for gene-arsenic interactions by first conducting a genome-wide search for SNPs that modify the effect of arsenic on molecular ("omic") phenotypes (i.e., gene expression and DNA methylation phenotypes, measured genome-wide) (Aim 1). Using this set of SNPs that interact with arsenic to influence molecular phenotypes, we will then test SNP-arsenic interactions in relation to arsenic-related health conditions: skin lesion status and diabetes-related phenotypes (Aim 2). As a secondary aim, we will attempt to identify SNPs that interact with arsenic to influence disease but were not selected in the Aim 1 "GxE-omic" screen by conducting conventional GWI analyses of our selected clinical phenotypes, using established "two-step" statistical approaches that leverage information on gene-environment correlation in cases and controls as well as marginal gene-disease associations. By using high-quality measures of arsenic exposure and restricting analyses to SNPs with enhanced probability of interaction with arsenic, we are highly likely to overcome the limitations of standard GWI approaches. Our team is ideally positioned to accomplish these aims, as we have conducted extensive research on the health effects of arsenic exposure and genetic susceptibility to arsenic toxicity and have extensive experience in environmental epidemiology, statistical genetics, and molecular genomics. We believe there is great promise in shifting the focus of GxE research from agnostic genome-wide interaction testing to understanding how genetic variants influence humans' response to an exposure at the molecular level. Our approach has very high potential to boost power for GWI research, enabling the identification of interactions that will enhance our understanding of disease etiology and our ability to develop interventions targeted at susceptible sub-populations. Moreover, the approach described here could potentially be used to investigate GxE interactions for a wide array of exposures and disease outcomes within our ongoing longitudinal study.