The different approaches to the genetic analysis of autoimmune thyroid disease

Abstract

Graves' disease and Hashimoto's thyroiditis are organspecific autoimmune disorders of multifactorial aetiology with a polygenic mode of inheritance. Familial clustering and twin studies provide evidence for a genetic predisposition. Three main approaches have been used in the search for susceptibility loci: population-based case-control studies, classical linkage analysis, and intrafamilial linkage disequilibrium. Case-control studies are a sensitive method of gene detection and the collection of subjects is resource-efficient. However, they require prior knowledge of a candidate gene and are prone to inconsistent results due to false positives that may arise from population mismatch. Linkage analysis is a powerful tool for detecting 'major' genes that does not require a candidate gene and is, therefore, a means of genome screening. This method, however, has limited power to detect genes of 'modest' effect, and the collection of sibpairs and multiple family members may be difficult. Intrafamilial linkage disequilibrium analysis is more sensitive than classical linkage analysis, requires only one affected offspring, and eliminates population mismatch. This approach has confirmed linkage disequilibrium of the HLA region with Graves' disease, previously not detected by linkage analysis. Knowledge of a candidate locus is required, however, and this method cannot, therefore, at present be used for genome screening. It is likely that a combination of all three approaches will be required to identify susceptibility loci for autoimmune thyroid disease.

Prevalence and Clinico-Epidemiology of Familial Graves' Disease in Japan based on Nationwide Epidemiologic Survey in 2001

“…For example, the ratios of mother-children to father-children and parents-daughter to parents-son were 3.0 (180/60) and 4.6 (83/18), respectively, which were similar to the female/male ratio of the whole GD family, 3.2 (360/114). It is well recognized that both GD and HT are frequently found in members of the same family, implying a shared genetic predisposition [19,20]. In the present study, approximately 8% of familial GD patients had HT in their first-degree relatives, supporting the existence of shared genes.…”

The Association and Linkage of the HLA-A2 Class I Allele with Autism

“…One study in particular that targeted the HLA region found no association with autism [36]. However, genome sib-pair linkage studies also have not detected HLA involvement in several autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, Graves' disease, and Hashimoto's thyroiditis, contrasted with other methods of genetic analysis that laid the groundwork for HLA-autoimmune associations [37][38][39][40].…”

Polymorphism of the CTLA-4 Gene Is Associated with Autoimmune Hypothyroidism in the United Kingdom

“…Although this report examined a variable (AT) n repeat sequence in the 39 untranslated region in exon 4 subsequent studies have focused more on the A-G repeat because, as an SNP, it is more suitable for case control study analysis (20) and it is in linkage disequilibrium with the (AT) n . Subsequent to the first report of an association with Graves' disease a number of investigators have reported association of the CTLA-4 gene with a variety of autoimmune disorders suggesting that the CTLA-4 gene region is acting as a susceptibility locus for the autoimmune disease process in general (21).…”