Mapping the major susceptibility loci for familial Graves' and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions.

The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of a complex interaction between predisposing genes and environmental triggers. The goals of the present study were to identify the susceptibility loci for GD and HT and to study the relationships between them. We performed a whole genome linkage study on a dataset of 56 multiplex, multigenerational AITD families (354 individuals), using 387 microsatellite markers. We identified 6 loci that showed evidence for linkage to AITD. Only one locus, on chromosome 6 [AITD-1; 80 centimorgans (cM)], was linked with both GD and HT [maximum LOD score (MLS), 2.9]. This locus was close to, but distinct from, the human leukocyte antigen region. One locus on chromosome 13 (HT-1; 96 cM) was linked to HT (MLS, 2.1), and another locus on chromosome 12 (HT-2; 97 cM) was linked to HT in a subgroup of the families (MLS, 3.8). Three loci showed evidence for linkage with GD: GD-1 on chromosome 14 (99 cM; MLS, 2.5), GD-2 on chromosome 20 (56 cM; MLS, 3.5), and GD-3 on chromosome X (114 cM; MLS, 2.5). Since GD-2 showed the strongest evidence for linkage to GD we fine-mapped this locus to a 1-cM interval between markers at 55 and 56 cM on chromosome 20. These results demonstrated that 1) Graves' and Hashimoto's diseases are genetically heterogeneous, with only one locus in common to both diseases on chromosome 6; 2) only one HT locus was identified in all families, probably due to heterogeneity of the HT phenotype; and 3) three loci were shown to induce genetic susceptibility to GD by interacting with each other. One of them (GD-2) was fine-mapped to a 1-cM interval.