Mapping the major susceptibility loci for familial Graves' and Hashimoto'sdiseases: Evidence for genetic heterogeneity and gene interactions

The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) an d Hashimoto's thyroiditis (HT), appear to develop as a result of a complex interaction between predisposing genes and environmental triggers. The goal s 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 familie s (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 bath GD and HT [maximum LOD score (MLS), 2.9]. This locus was close to, but distinct from, the human l eukocyte antigen region. One locus on chromosome 13 (HT-1; 96 cM) was linke d to HT (MLS, 2.1), and another locus on chromosome 12 (HT-2; 97 cM) was li nked to HT in a subgroup of the families (MLS, 3.8). Three loci showed evid ence 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-mappe d this locus to a 1-cM interval between markers at 55 and 56 cM on chromoso me 20. These results demonstrated that 1) Graves' and Hashimoto's diseases are genetically heterogeneous, with only one locus in common to both diseas es on chromosome 6; 2) only one HT locus was identified in all families, pr obably due to heterogeneity of the HT phenotype; and 3) three loci were sho wn to induce genetic susceptibility to GD by interacting with each other. O ne of them (GD-2) was fine-mapped to a 1-cM interval.