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Quantitative Trait Loci Associated with Elevated Thyroid-Stimulating Hormone in the Wistar-Kyoto Rat

Departments of Psychiatry and Behavioral Science (A.E.B., L.C.S., N.A., E.E.R.) and Endocrinology, Metabolism, and Molecular Medicine (A.E.B., P.K., L.J.), Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611; Department of Neurobiology and Physiology (L.C.S., N.A., J.S.T.), Howard Hughes Medical Institute (N.A., J.S.T.), Northwestern University, Evanston, Illinois 60208; and The Jackson Laboratory (G.C.), Bar Harbor, Maine 04609

Address all correspondence and requests for reprints to: Dr. Eva Redei, Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: e-redei{at}northwestern.edu.

Thyroid hormones are essential for the regulation of developmental and physiological processes. The genetic factors underlying naturally occurring variability in mammalian thyroid function are, however, only partially understood. Genetic control of thyroid function can be studied with animal models such as the inbred Wistar-Kyoto (WKY) rat strain. Previous studies established that WKY rats have elevated TSH, slightly elevated total T₃, and normal total T₄ levels compared with Wistar controls. The present study confirmed a persistent 24-h elevation of TSH in WKY rats compared with the Fisher 344 (F344) rat, another inbred strain. Acute T₃ challenge (25 µg/100 g body weight ip) suppressed serum TSH and T₄ levels in both strains. Quantitative trait locus analysis of elevated TSH in a reciprocally bred WKY x F344 F2 population identified one highly significant locus on chromosome 6 (LOD = 11.7, TSH-1) and one suggestive locus on chromosome 5 (LOD = 2.3, TSH-2). The confidence interval of TSH-1 contains the TSH receptor and type 2 deiodinase genes, and TSH-2 contains the type 1 deiodinase gene. The WKY alleles of each gene contain sequence alterations, but additional studies are indicated to identify the specific gene or genes responsible for altered regulation of the thyroid axis. These findings suggest that one or more genetic alterations within the TSH-1 locus significantly contribute to the altered thyroid function tests of the WKY rat.

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