Thyroid hormones are critically important in many metabolic and physiological processes. However, there is very little information on how normal variation in thyroid hormone phenotypes is genetically mediated. The overall objective of this proposal is to detect genetic effects on normal thyroid hormone variation in an animal model, the baboon, by statistical genetic analysis of pedigree data. Complex segregation analysis will be used to determine the effects of major genes, polygenic factors, and a known polymorphic candidate locus on several quantitative dimensions of thyroid hormone variation including thyroid hormone secretion, thyroid hormone metabolism, thyroid hormone transport, and thyroid hormone action. Specifically, serum concentrations of thyroglobulin, total thyroxine, free thyroxine, total triiodothyronine, free triiodothyronine, reverse triiodothyronine, thyroxine-binding globulin, sex hormone binding globulin, and osteocalcin will be measured in 600 pedigreed baboons. Each animal's genotype at a polymorphic candidate locus, thyroxine- binding globulin (TBG), will be assessed. Using quantitative genetic methods, the heritabilities of each trait and the genetic correlations between traits will be estimated. Complex segregation analysis will be used to detect major genes influencing these thyroid hormone phenotypes and to examine the joint effects of major genes, polygenes, and the TBG polymorphism. Extensions of segregation analysis will be used to detect differential expression of genotypes as a function of covariates such as sex and age. Current statistical genetic techniques will be extended to allow for multiple quantitative phenotypes and new multivariate statistical genetic methods will be developed. These methods will provide increased power to detect subtle effects of major loci on quantitative traits. These multivariate segregation analysis methods will be used to detect pleiotropic effects of major genes influencing different aspects of thyroid hormone variation and to examine interactions between loci. The proposed project will increase our knowledge about the genetic determinants of thyroid hormone variation, provide information on the extent of genetic covariation among related thyroid hormone phenotypes, help establish the baboon as a model for endocrine genetics, and provide new tools for multivariate genetic analysis.
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