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Genetic Loci Linked to Pituitary-Thyroid Axis Set Points: A Genome-Wide Scan of a Large Twin Cohort

Department of Endocrinology and Diabetes (V.P., S.G.W., S.J.B., E.M.L., J.P.W.), Sir Charles Gairdner Hospital, and Pathwest Laboratory Medicine Western Australia (E.M.L., S.J.F.), Nedlands, Western Australia, and School of Medicine and Pharmacology (V.P., S.G.W., J.P.W.), University of Western Australia, Crawley, Western Australia, Australia 6009; Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology (V.P.), University of Bristol, Bristol BS13NY, United Kingdom; Twin Research and Genetic Epidemiology Unit (S.G.W., T.D.S., B.S.K., M.F., J.B.R., G.L.S.), King’s College London, London SE5 9PJ, United Kingdom; Reed Biomedical (P.W.R.), Rotorua, New Zealand; and Department of Genomic Medicine (M.F.), Imperial College, London SW7 2AZ, United Kingdom

Address all correspondence and requests for reprints to: Clinical A/Professor John P. Walsh, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 6009. E-mail: john.walsh{at}health.wa.gov.au.

Objective: Previous studies have shown that circulating concentrations of TSH, free T₄, and free T₃ are genetically regulated, but the genes responsible remain largely unknown. The aim of this study was to identify genetic loci associated with these parameters.

Design: We performed a multipoint, nonparametric genome-wide linkage scan of 613 female dizygotic twin pairs. All subjects were euthyroid (TSH 0.4–4.0 mU/liter) with negative thyroid peroxidase antibodies and no history of thyroid disease. The genome scan comprised 737 microsatellite markers supplemented with dinucleotide markers. Data were analyzed using residualized thyroid hormone data after adjustment for age, smoking, and body mass index.

Results: Multipoint linkage analysis gave linkage peaks for free T₄ on chromosome 14q13 and 18q21 [logarithm of odds (LOD) 2.4–3.2]; TSH on chromosomes 2q36, 4q32, and 9q34 (LOD 2.1–3.2); and free T₃ on chromosomes 7q36, 8q22, and 18q21 (LOD 2.0–2.3).

Conclusions: This study has identified eight genomic locations with linkage of LOD of 2.0 or greater. These results should enable targeted positional candidate and positional cloning studies to advance our understanding of genetic control of the pituitary-thyroid axis.