VARIANCE COMPONENTS MODELS FOR MAPPING QTLS

我们建议发展我们在方差分量方法上的工作，使用关联和连锁方法来定位人类复杂性状的QTL。我们将为我们现有的模拟和分析计划制作文档，并将其整合到一个全面的一揽子计划中。我们将扩展我们的方法，包括QTL与环境和其他基因座的互作，即X基因与环境互作和上位性。我们将包括多变量分析方面的最新工作，以期增加统计能力。我们将把我们的分析方法推广到有限数量的亲属，而不是同胞。我们建议的一个特别新颖的方面是开发一种涉及兄弟姐妹的新的关联测试，该测试控制人口分层，并通过使用在连续表型上获得极端分数的兄弟姐妹来增加统计能力。这一新的检验将被嵌入到最大似然方差分量方法中，其中关联将通过兄弟姐妹方法来建模，而关联将通过协方差矩阵来建模。这种联合的连锁-关联测试将产生关于复杂性状的遗传结构的新信息。传递不平衡检验将被严格开发用于连续性状，无论是单独使用还是与我们新的兄弟姐妹关联测试结合使用。在我们的新建议中，重点是涉及选定样本和最大似然方差分量分析的新方法，以实现复杂性状基因定位的综合方法。

We propose to develop our work on variance components methods for mapping QTLs for human complex traits using both association and linkage approaches. We will produce documentation for our existing programs for both stimulation and analysis and integrate these into a comprehensive package. We will extend our approach to include the interaction of QTLs with both the environment and with other loci, i.e., genotype X environment interaction and epistasis. We will include recent work on multivariate analysis with a view to increasing statistical power. We will generalize our analytic approach to a limited number of relatives other than sibs. One particularly novel aspect of our proposal is the development of a new test of association involving siblings which controls for population stratification and increases statistical power through the use of siblings selected for extreme scores on a continuous phenotype. This new test will be embedded in a maximum likelihood variance components approach where association will be modeled through sibling means and linkage will be modeled through the covariance matrix. This combined linkage-association test will yield novel information about the genetic architecture of complex traits. The transmission disequilibrium test will be rigorously developed for use with continuous traits either separately or combined with our new sibling test of association. The emphasis in our new proposal is on new approaches involving selected samples and maximum likelihood variance components analysis in order to achieve an integrated approach to mapping genes for complex traits.