The different approaches to the genetic analysis of autoimmune thyroid disease

Graves' disease and Hashimoto's thyroiditis are organ-specific autoimmune d isorders of multifactorial aetiology with a polygenic mode of inheritance. Familial clustering and twin studies provide evidence for a genetic predisp osition Three main approaches have been used in the search for susceptibili ty loci: population-based case-control studies, classical linkage analysis, and intrafamilial linkage disequilibrium. Case-control studies are a sensi tive method of gene detection and the collection of subjects is resource-ef ficient. However, they require prior knowledge of a candidate gene and are prone to inconsistent results due to false positives that may arise from po pulation mismatch. Linkage analysis is a powerful tool for detecting 'major ' genes that does not require a candidate gene and is, therefore, a means o f genome screening. This method, however, has Limited power to detect genes of 'modest' effect, and the collection of sibpairs and multiple family mem bers may be difficult. Intrafamilial linkage disequilibrium analysis is mor e sensitive than classical linkage analysis, requires only one affected off spring, and eliminates population mismatch. This approach has confirmed Lin kage disequilibrium of the HLA region with Graves disease, previously not d etected by linkage analysis. Knowledge of a candidate locus is required, ho wever, and this method cannot, therefore, at present be used for genome scr eening. It is likely that a combination of all three approaches will be: re quired to identify susceptibility loci for autoimmune thyroid disease.