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Gene-environment interaction vs quantile-dependent penetrance of established SNPs

基因-环境相互作用与已建立的 SNP 的分位数依赖性外显率

基本信息

批准号：
8619627
负责人：
PAUL T WILLIAMS
金额：
$ 4.72万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Gene-environment interactions may be defined as a genotype's phenotypic expression being altered by the environment, e.g., the weaker effect of FTO polymorphisms on body mass index (BMI) in exercisers compared to non-exercisers. However, our preliminary analyses suggest that the phenotypic expressions of FTO polymorphisms are diminished in lean vis-a-vis overweight individuals. This suggests an alternative interpretation (Figure 1). Based on the fact that exercisers are leaner than non-exercisers, we hypothesize that physical activity affects BMI, which in turn affects FTO gene expression, rather than exercise affecting FTO gene expression directly. Our preliminary analyses of lipoproteins and BMI in 1800 subjects suggest that a genotype's phenotypic expression often increases with the quantile of the phenotype, i.e., when the value of the phenotype is high relative to its distribution in the population. We refer to this dependence as quantile- dependent penetrance. This dependence differs from the standard regression model, which assumes that the same relationship between the dependent and independent variables (e.g., phenotype vs. genotype) applies to all quantiles of the dependent variable. We propose to apply quantile regression to data available through the NHLBI Candidate-Gene Association Resource (CARe), DBGaP, and other studies to assess whether quantile-dependent penetrance applies to most other genotype-phenotype relationships. Although our preliminary analyses lacked the statistical power to assess this phenomenon for individual SNPs, its demonstration in genetic risk scores suggests that the majority of SNP effects must also be quantile dependent. We will also test whether prior assertions of gene- environment interactions are attributable to quantile-dependent penetrance, whether allowing the genotypic expression to vary with the percentile of the trait distribution significantly increases the phenotypic variances explained, and whether quantile-dependent penetrance can be extended to SNP-SNP interactions. This proposal is hypothesis driven; i.e., we hypothesize that most genotype-phenotype associations increase substantially with the percentile of the phenotype. This hypothesis is based upon the premise that the most important gene-environment interaction involves an individual's own physiological environment within which the genes are expressed. The lowest to highest percentiles of a trait's distribution represent a range of physiologic parameters, genetic make-ups, and gene-gene interactions whose presence may be essential for the genetic variant to be expressed. To our knowledge, quantile-dependent penetrance has not been proposed as a primary basis for genotype-phenotype relationships, or as an alternative to gene-environment interactions.

描述（由申请人提供）：基因-环境相互作用可以定义为基因型的表型表达被环境改变，例如，与不锻炼者相比，FTO 多态性对锻炼者体重指数（BMI）的影响较弱。然而，我们的初步分析表明，与超重个体相比，瘦个体中 FTO 多态性的表型表达有所减弱。这提出了另一种解释（图 1）。基于运动者比不运动者更瘦的事实，我们假设体力活动影响BMI，进而影响FTO基因表达，而不是运动直接影响FTO基因表达。我们对 1800 名受试者的脂蛋白和 BMI 进行的初步分析表明，基因型的表型表达通常随着表型的分位数而增加，即当表型的值相对于其在人群中的分布而言较高时。我们将这种依赖性称为分位数依赖性外显率。这种依赖性与标准回归模型不同，标准回归模型假设因变量和自变量之间的相同关系（例如表型与基因型）适用于因变量的所有分位数。我们建议将分位数回归应用于通过 NHLBI 候选基因关联资源 (CARe)、DBGaP 和其他研究获得的数据，以评估分位数依赖性外显率是否适用于大多数其他基因型-表型关系。尽管我们的初步分析缺乏统计能力来评估单个 SNP 的这种现象，但其在遗传风险评分中的证明表明，大多数 SNP 效应也必须是分位数相关的。我们还将测试基因-环境相互作用的先前断言是否可归因于分位数依赖性外显率，允许基因型表达随性状分布的百分位数变化是否显着增加所解释的表型方差，以及分位数依赖性外显率是否可以扩展到SNP-SNP相互作用。该提议是假设驱动的；也就是说，我们假设大多数基因型-表型关联随着表型的百分位而显着增加。该假设基于以下前提：最重要的基因-环境相互作用涉及个体自身的基因表达的生理环境。性状分布的最低到最高百分位代表一系列生理参数、遗传组成和基因-基因相互作用，它们的存在对于遗传变异的表达可能是必需的。据我们所知，分位数依赖性外显率尚未被提议作为基因型-表型关系的主要基础，或作为基因-环境相互作用的替代方案。