Genome-wide scan for context-dependent associations with ischemic heart disease a

描述（由申请人提供）：对植物、模式生物和人类的广泛研究表明，基因-环境（GxE）相互作用在复杂性状变异中几乎无处不在。人类遗传学家有一长串基因变异，这些变异定义了一种疾病风险升高，而这种疾病的表现只有在特定的环境损害下才会触发。目前缺乏的是应用一个健全的统计框架，在全基因组范围内揭示环境背景在形成遗传变异表现中的作用。尽管混合线性模型在这类问题上很流行，但这些模型的许多假设都以一种既可以降低测试的能力又可以产生误报的方式被违背。我建议使用患者规则诱导法（PRIM）开发和应用在环境背景下检测snp -疾病关联的策略。PRIM方法不仅提供了一种发现环境依赖的基因型效应的方法，而且还通过评估环境依赖对疾病风险的影响来改善表型预测。我将开发PRIM的扩展，用于执行上下文依赖的全基因组扫描，并且通过广泛的模拟，我将测试和验证该方法。这项工作将旨在确定在不同环境背景下（如吸烟、高血压、肥胖）缺血性心脏病和高密度脂蛋白水平中发挥作用的常见和罕见遗传变异。在环境依赖性强的情况下，对携带风险等位基因的个体有针对性地改变环境风险可能对降低疾病风险特别有效。

DESCRIPTION (provided by applicant): Extensive research in plants, model organisms, and humans has demonstrated the near ubiquity of gene-environment (GxE) interactions in complex trait variation. Human geneticists have a long list of genetic variants that define an elevated disease risk whose manifestation is only triggered under particular environmental insults. What is lacking is the application of a sound statistical framework for uncovering, at a genome-wide scale, the role of environmental context in shaping the manifestation of genetic variation. As popular as mixed linear models are for problems of this sort, many of the assumptions of these models are violated in a way that can both reduce the power of the tests and generate false positives. I propose to develop and apply strategies for detecting SNP-disease associations in an environmental context using the Patient Rule Induction Method (PRIM). The PRIM approach not only offers a way to discover context-dependent genotype effects, but with a view towards improving prediction of the phenotype through assessment of the impact of context dependence on disease risk. I will develop extensions of PRIM for performing genome-wide scans for context dependence, and through extensive simulations I will test and validate the approach. This work will aim to identify both common and rare genetic variants that play a role in ischemic heart disease and high density lipoprotein levels in different environmental contexts (such as smoking, high blood pressure, obesity). In instances of strong context-dependence, targeted modification of environmental risks for individuals who harbor risk alleles may be especially efficacious to reduce the risk of disease.