Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions
Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions
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DOI：
10.1086/302782
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发表时间：
2000-02-01
影响因子：
9.8
通讯作者：
Laird, NM
中科院分区：
文献类型：
--
作者：
Lunetta, KL;Faraone, SV;Laird, NM
我们扩展了以家庭为基础的关联和连锁测试的方法，以允许受试者的表型变化和将协变量纳入关联的一般评分测试。我们使用标准的关联模型的表型和任何数量的预测。Fire然后构建一个评分统计量，使用表型分布的似然性，给定基因型。分数的分布被计算为后代基因型的函数，以后代和父母的亲本基因型和性状值为条件。这种方法提供了一个自然延伸的传输/不平衡测试到任何表型和多个基因或环境因素，并允许基因-基因和基因-环境相互作用的研究。当性状在受试者之间变化或协变量包括在关联模型中时，得分统计取决于一个或多个滋扰参数。我们建议两种方法来获得参数估计：（1）选择的估计，最大限度地减少测试统计量的方差和（2）最大化的统计量在一个滋扰参数，并使用一个校正的P值。我们将我们的方法应用于注意力缺陷/多动障碍的家庭样本，并提供了如何将协变量和基因-环境和基因-基因相互作用的例子。
We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a phenotype and any number of predictors. Fire then construct a score statistic, using likelihoods for the distribution of phenotype, given genotype. The distribution of the score is computed as a function of offspring genotypes, conditional on parental genotypes and trait values for offspring and parents. This approach provides a natural extension of the transmission/disequilibrium test to any phenotype and to multiple genes or environmental factors and allows the study of gene-gene and gene-environment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one or more nuisance parameters. We suggest two approaches for obtaining parameter estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter and using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how covariates and gene-environment and gene-gene interactions can be incorporated.