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Genome-Wide Linkage Analysis Reveals Evidence for Four New Susceptibility Loci for Familial Euthyroid Goiter

III. Medical Department (Y.B., S.N., A.R., R.P.), University of Leipzig, 04103 Leipzig, Germany; Gene Mapping Center (B.M., F.R., P.N.), Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany; Department of Endocrinology (T.B., L.H.), Odense University Hospital, 5000 Odense, Denmark; Department of Internal Medicine (P.L.), Faculty of Medicine, P. J. Safárik University, 040 60 Kosice, Slovakia; and Institute of Medical Genetics (P.N.), Charité University Hospital, Humboldt University, 10099 Berlin, Germany

Address all correspondence and requests for reprints to: Ralf Paschke, M.D., III. Medical Department, University of Leipzig, Ph.-Rosenthal-Straße 27, 04103 Leipzig, Germany. E-mail: pasr{at}medizin.uni-leipzig.de.

Euthyroid goiter is characterized by diffuse or nodular enlargement of the thyroid gland. Iodine deficiency and cigarette smoking have been identified as important environmental factors. However, family and twin pair studies suggest a strong genetic predisposition. Therefore, we performed the first extended genome-wide scan to identify susceptibility loci that predispose for euthyroid goiter using 450 microsatellite markers in 18 extended Danish, German, and Slovakian families. Parametric and nonparametric multipoint linkage analyses were performed. The highest nonparametric LOD scores were obtained for chromosomes 2q and 3p with values of 2.54 at D2S1363 and 2.25 at D3S3038, respectively. Assuming heterogeneity and dominant inheritance, heterogeneity LOD scores (HLOD) of 2.71 and 1.94 were calculated for 2q and 3p, respectively. Furthermore, nonparametric LOD scores of 1.87 (HLOD 1.39) at D7S1808 on 7q and 1.79 (HLOD 1.80) at D8S264 on 8p were obtained. Haplotyping of families contributing to the linkage signals revealed four families compatible with a putative locus on 3p and one family each showing strict cosegregation with the loci on 2q, 7q, and 8p. The four novel candidate loci corroborate the assumed heterogeneity in the etiology of euthyroid familial goiter. For the first time, a more prevalent putative locus, present in 20% of the families investigated, was identified.

This work was supported by a grant from the Deutsche Forschungsgemeinschaft to S.N. (DFG/NE 844/1-1), the Agnes and Knut Mörk Foundation, and the German Federal Department of Education and Research to P.N. (01KW9967).

Abbreviations: fT₃, Free T₃; fT₄, free T₄; HLOD, heterogeneity LOD scores; MNG, multinodular goiter; NPL, nonparametric LOD; PDS, pendrin; RTH, thyroid hormone resistance; StatE, Statistic E; TG, thyroglobulin; THRB, thyroid hormone receptor ß; TPO, thyroid peroxidase; TRIP6, thyroid hormone receptor interactor 6; TSHR, TSH receptor.

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