ANALYSIS OF THE THYROTROPIN RECEPTOR AS A CANDIDATE GENE IN FAMILIAL GRAVES-DISEASE

Familial clustering of Graves' disease indicates a genetic etiology. S earches for genetic factors additional to the known human leukocyte an tigen (HLA) association have implicated the gene for the TSH receptor (TSHR). We analyzed the linkage and association among three recently d escribed microsatellite markers within the TSHR introns in Graves' dis ease in large multiply affected Welsh and English families (223 member s, 44 affected individuals). Linkage analysis under a dominant model s trongly rejected the hypothesis that TSHR is linked to Graves' disease in these families (lod score = -4.53). More detailed analyses also fa iled to provide evidence for linkage; these included combined segregat ion and linkage analysis, correction for HLA-DR3 status, allowance for the levels of thyroid autoantibodies in unaffected pedigree members, consideration of a recessive model for the disease, and linkage disequ ilibrium between disease and marker alleles. We also considered the po ssibility of a genetic heterogeneity of Graves' disease and thus analy zed separately the different families with a similar result. Although these results cannot eliminate a minor role of the TSHR gene locus in the genetics of Graves' disease, they argue against it being a major g enetic determinant in this pathology.