Robust Test for Genetic Effect in Presence of Interaction with Age-At-First-Drink

与首次饮酒年龄相互作用存在遗传效应的稳健测试

• 批准号: 8581338
• 负责人: Tatiyana V. Apanasovich
• 金额: $ 7.44万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581338
• 关键词: Accounting; Adult; Age; Alcohol consumption; Alcohol dependence; Behavior Disorders; Cessation of life; Code; Communities; Complex; Computer software; DSM-IV; Data; Detection; Economic Inflation; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Etiology; Exposure to; Freedom; Funding; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic screening method; Genomics; Goals; Individual Differences; Internet; Knowledge; Language; Lead; Link; Logistic Regressions; Logistics; Methodology; Modeling; Odds Ratio; Other Genetics; Population; Programming Languages; Public Health; Research Personnel; Resources; Risk; Risk Factors; Role; Simulate; Specific qualifier value; Statistical Computing; Substance Use Disorder; Sum; Susceptibility Gene; Test Result; Testing; Twin Studies; United States; Variant; addiction; alcohol involvement; base; database of Genotypes and Phenotypes; design; drinking; flexibility; gene environment interaction; genetic analysis; genetic association; genetic variant; meetings; public health relevance; response; trait; underage drinking; user friendly software

DESCRIPTION (provided by applicant): Multiple epidemiological studies imply that alcohol dependence is a complex behavioral disorder influenced by both genetic and environmental factors. Hence, to add information about environmental exposure to its genetic association designs is the appropriate strategy recommended for the following reasons. First, the knowledge of the interplay between genetic and environmental factors is essential for a complete understanding of the etiology of alcohol dependence. Second, accounting for heterogeneity of genetic effects due to interaction can be vital for the validity and enhanced power of the primary hypothesis in association testing. The most commonly cited environmental contributor to risk of alcohol dependence is age at first drink. This association replicated in many epidemiological studies suggests that underage drinking is linked to increased alcohol involvement and dependence. Twin studies have recently demonstrated that age at first drink moderates genetic influences on alcohol dependence. Therefore, age at first drink is an ideal candidate for an environmental modifier of genetic vulnerability in association studies. In the presence of a continuous environmental exposure, the investigator needs to carefully select the functional form of the association between the factor and the logarithm of the odds ratio of alcohol dependence. Otherwise, the misspecified main effect would lead to a dramatic inflation of Type 1 error rates in standard logistic regression tess of genetic associations. There is also overwhelming evidence that confirms the role of familial influences on age at first drink, which suggests the presence of gene-environment association. Hence tests that exploit gene-environment independence (i.e. case-only) and do not require that the main effect of the environment be specified, are susceptible to biased results and cannot be used. To relax the assumption about a parametric relationship between risk and exposure as well as reduce the dramatic effects of its misspecification, a nonparametric term is introduced into a model. Score testing approach is used to avoid numerical difficulty associated with parameter estimation under general nonparametric models. The resulting tests are straightforward to implement, they maintain the desired Type 1 error level. Moreover, the proposed tests gain substantial power when there is an interaction between genetic and environmental factors and lose little power when there is none. The proposed methodology will be applied to the data collected as part of Study of Addiction: Genetics and Environment (SAGE) available through the database of Genotypes and Phenotypes (dbGaP). However, flexibility of the proposed methodology as well as availability of the software will result in easy adaptation to other genetic association studies with a continuous environmental exposure.

描述(由申请人提供)： 多项流行病学研究表明，酒依赖是一种受遗传和环境因素影响的复杂行为障碍。因此，将有关环境暴露的信息添加到其遗传关联设计中是推荐的适当策略，原因如下。首先，了解遗传和环境因素之间的相互作用对于全面了解酒精依赖的病因至关重要。其次，考虑到交互作用导致的遗传效应的异质性对于关联检验中主要假设的有效性和增强的力量至关重要。最常被提及的酒精依赖风险的环境因素是第一次饮酒的年龄。在许多流行病学研究中重复了这种联系，表明未成年人饮酒与酒精参与和依赖的增加有关。双胞胎研究最近证明，第一次饮酒的年龄缓和了对酒精依赖的遗传影响。因此，在关联性研究中，首次饮酒年龄是遗传易感性的环境修饰物的理想候选者。在持续环境暴露的情况下，研究人员需要仔细选择该因素与酒精依赖优势比的对数之间的联系的函数形式。否则，错误指定的主效应将导致基因关联的标准Logistic回归测试中类型1错误率的戏剧性膨胀。也有压倒性的证据证实了家庭影响在第一次饮酒时对年龄的影响，这表明存在基因-环境关联。因此，利用基因-环境独立性(即仅限于案例)且不要求具体说明环境的主要影响的测试很容易受到有偏见的结果的影响，不能使用。为了放松对风险和暴露之间参数关系的假设，并减少其错误说明的显著影响，在模型中引入了一个非参数项。在一般非参数模型下，为了避免参数估计的数值困难，采用了Score检验法。得到的测试很容易实现，它们保持了所需的类型1错误级别。此外，当遗传和环境因素相互作用时，拟议的测试获得了相当大的动力，而在没有遗传因素和环境因素的情况下，损失很小。建议的方法将应用于作为成瘾研究的一部分收集的数据：遗传学和环境(SAGE)，可通过基因型和表型数据库(DBGaP)获得。然而，拟议方法的灵活性以及软件的可用性将使 适应持续环境暴露的其他遗传关联研究。