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The genetics of autoimmune Addison disease: past, present and future

Abstract

Autoimmune Addison disease is an endocrinopathy that is fatal if not diagnosed and treated in a timely manner. Its rarity has hampered unbiased studies of the predisposing genetic factors. A 2021 genome-wide association study, explaining up to 40% of the genetic susceptibility, has revealed new disease loci and reproduced some of the previously reported associations, while failing to reproduce others. Credible risk loci from both candidate gene and genome-wide studies indicate that, like one of its most common comorbidities, type 1 diabetes mellitus, Addison disease is primarily caused by aberrant T cell behaviour. Here, we review the current understanding of the genetics of autoimmune Addison disease and its position in the wider field of autoimmune disorders. The mechanisms that could underlie the effects on the adrenal cortex are also discussed.

Key points

  • Autoimmune Addison disease (AAD) is an oligogenic complex disease.

  • Genetic risk loci for AAD largely overlap with known autoimmune comorbidities.

  • In particular, HLA and autoimmune regulator (AIRE) variants predispose to AAD.

  • Probable functional elements of genetic risk variants highlight a T cell aetiology for AAD.

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Fig. 1: AAD risk loci.
Fig. 2: Linkage disequilibrium patterns of variants associated with autoimmune Addison disease.
Fig. 3: Circular plot of GWAS associations in selected autoimmune diseases.
Fig. 4: AAD risk loci are enriched in T cell education and regulation.

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E.C.R. researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission. E.S.H. contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Ellen C. Røyrvik.

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LDlink: https://ldlink.nci.nih.gov

The GWAS Catalog: https://www.ebi.ac.uk/gwas/

Glossary

Linkage disequilibrium

Allelic states at separate genetic loci being correlated beyond what is predicted by their respective frequencies.

Expression quantitative trait loci

(eQTL). Loci at which variants affect the expression of one or more genes.

Suggestive significance level

Defined here as P < 1e−5, P values below which a genetic association signal investigation is warranted despite not reaching the commonly used genome-wide significance threshold.

Genome-wide significance level

P < 5e−8, the P value threshold for statistical significance, based on the estimated number of common, independent single nucleotide polymorphisms in the human genome.

Background range

Defined here heuristically as within the indistinguishable mass of high P values in a Manhattan plot; in the current case 0.01 or larger.

Prioritized gene

Defined here as the gene predicted to be the causative element of any given association signal.

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Røyrvik, E.C., Husebye, E.S. The genetics of autoimmune Addison disease: past, present and future. Nat Rev Endocrinol 18, 399–412 (2022). https://doi.org/10.1038/s41574-022-00653-y

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