VARIANCE COMPONENTS MODELS FOR MAPPING QTLS

我们建议利用关联和连锁两种方法来开发人类复杂性状qtl的方差成分方法。我们将为现有的增产和分析项目制作文件，并将其整合到一个综合包中。我们将扩展我们的方法，包括qtl与环境和其他位点的相互作用，即基因型X环境相互作用和上位性。我们将包括最近在多元分析方面的工作，以提高统计能力。我们将把我们的分析方法推广到除兄弟姐妹以外的有限数量的亲属。我们的建议的一个特别新颖的方面是开发了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选择极端分数的兄弟姐妹来增加统计能力。这个新的测试将嵌入到最大似然方差成分方法中，其中关联将通过兄弟平均数建模，而联系将通过协方差矩阵建模。这种联合连锁关联测试将产生有关复杂性状遗传结构的新信息。传递不平衡检验将被严格发展，以用于连续性状单独或与我们的新兄弟关联检验相结合。在我们的新建议的重点是新的方法，包括选择样本和最大似然方差成分分析，以实现一个综合的方法来定位复杂性状的基因。

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.