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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK044297-02
Application #
3464550
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1992-09-30
Project End
1997-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Southwest Foundation for Biomedical Research
Department
Type
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78245
Martin, Lisa J; Cole, Shelley A; Hixson, James E et al. (2002) Genotype by smoking interaction for leptin levels in the San Antonio Family Heart Study. Genet Epidemiol 22:105-15
Martin, Lisa J; Mahaney, Michael C; Almasy, Laura et al. (2002) Leptin's sexual dimorphism results from genotype by sex interactions mediated by testosterone. Obes Res 10:14-21
Martin, Lisa J; Mahaney, Michael C; Almasy, Laura et al. (2002) A quantitative trait locus on chromosome 22 for serum leptin levels adjusted for serum testosterone. Obes Res 10:602-7
Zhang, W; Tapper, W; Collins, A et al. (2001) A tournament of linkage tests in complex inheritance. Hum Hered 52:140-8
Comuzzie, A G; Almasy, L; Cole, S A et al. (2000) Linkage exclusion analysis of the chromosome 11 region containing UCP2 and UCP3 with obesity-related phenotypes in Mexican Americans. Int J Obes Relat Metab Disord 24:1065-8
Williams, J T; Van Eerdewegh, P; Almasy, L et al. (1999) Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results. Am J Hum Genet 65:1134-47
Williams, J T; Blangero, J (1999) Comparison of variance components and sibpair-based approaches to quantitative trait linkage analysis in unselected samples. Genet Epidemiol 16:113-34
Duggirala, R; Blangero, J; Almasy, L et al. (1999) Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet 64:1127-40
Duggirala, R; Mitchell, B D; Blangero, J et al. (1999) Genetic determinants of variation in gallbladder disease in the Mexican-American population. Genet Epidemiol 16:191-204
Hixson, J E; Almasy, L; Cole, S et al. (1999) Normal variation in leptin levels in associated with polymorphisms in the proopiomelanocortin gene, POMC. J Clin Endocrinol Metab 84:3187-91

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