VARIANCE COMPONENTS MODELS FOR MAPPING QTLS

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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.