MAPPING OF A MAJOR SUSCEPTIBILITY LOCUS FOR GRAVES-DISEASE (GD-1) TO CHROMOSOME 14Q31

The autoimmune thyroid diseases (AITD), encompassing Graves' disease ( GD) and Hashimoto's thyroiditis (HT), occur in genetically susceptible individuals. In order to identify the:AITD susceptibility genes, we h ave studied DNA markers in the regions of 8 candidate genes: (1) the H LA region, (2) the TSH receptor, (3) thyroid peroxidase, (4) thyroglob ulin, (5) IDDM-4, (6) IDDM-5, CI) Immunoglobulin heavy chain gene and (8) CTLA-4. One hundred and seven subjects from 19 informative familie s were studied, 14 subjects had GD and 32 subjects had HT. LOD scores were maximized assuming both dominant and recessive modes of inheritan ce. No linkage was found for any marker in patients with HT. Inpatient s with GD, negative LOD scores were obtained for all the candidate gen es, except for markers in the TSH receptor region on chromosome 14q31. Positive LOD scores were found for several markers on 14q31. Marker D 14S81 gave the highest score (Z max = 2.05, theta = 0.01) assuming a d ominant mode of inheritance and a penetrance of 0.8. These data confir m our previous observations of a lack of a necessary disease locus for AITD in the HLA gene region. Further, the data suggest the presence o f an important susceptibility gene on 14q31 but at a considerable dist ance from the TSH receptor gene.