STATISTICAL GENETICS OF THYROID HORMONES

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.