Genetic risk factors in autoimmune Addison's disease

Abstract

Autoimmune Addison’s disease is the most common form of primary adrenal insufficiency in the Western world. The low prevalence of the disease has hampered large-scale unbiased genetic studies where the entire genome could be examined at once. By combining the two largest biobanks of DNA from patients with autoimmune Addison’s disease, we identified in Paper I nine independent risk loci with a genome-wide association study of 1223 patients and 4097 geographically matched controls. These results explained up to 41% of the heritability of the disease, which, in a twin study, has been estimated to be as high as 0.97 [95% CI 0.88-0.99].

In Paper II, we derived a polygenic risk score for autoimmune Addison’s disease with the same dataset from the first study. The polygenic risk score enabled an estimation of disease susceptibility at the individual level and the discrimination of other etiologies of primary adrenal insufficiency, uncovering cases previously presumed to have the autoimmune form of Addison’s disease.

In Paper III, we explored the use of our polygenic risk score to efficiently triage patients who may benefit most from whole-genome sequencing to achieve the correct diagnosis and appropriate clinical management of the disease. Monogenic forms of primary adrenal insufficiency were found in 5 out of 35 cases with low polygenic risk score for autoimmune Addison’s disease, and we found an additional of three cases with suspected monogenic disease. This study highlights the potential of polygenic risk score as a tool to in the clinical evaluation of primary adrenal insufficiency.

In summary, this thesis sheds light on the genetic risk factors behind the development of autoimmune Addison’s disease and their potential utility as diagnostic classifiers. Future studies are warranted to further our understanding of the biological role of the associated genetic risk factors.