GWAS Uncovers Variants Associated With Increased Risk of Addison Disease

Researchers identified variants of 9 genes that increase the risk of developing the rare disease.

By conducting a genome-wide association study (GWAS) based on the largest collection of samples from patients with autoimmune Addison disease (AAD), researchers identified variants of 9 genes that increase the risk of developing the rare disease.

Findings, published in Nature Communications, “highlight the importance of central immune tolerance in the development of AAD,” authors wrote. In patients with AAD, the immune system attacks the adrenal glands necessitating lifelong steroid hormone replacement therapy. If left untreated, the disease—which is the most common cause of primary adrenal failure in the Western world—can be fatal.

The condition only affects from 5 individuals per 1 million in Japan and over 200 people per 1 million in Nordic countries. Due to its low prevalence and complex inheritance, successful genetic studies on the disease are scarce, leading to a paucity of information on genetic factors contributing to disease development.

To better understand these factors, researchers analyzed data from the Swedish and Norwegian Addison Registries and compared findings with samples from healthy controls recruited from blood donor centers across the 2 countries. Investigators isolated DNA from blood samples and conducted genome-wide genotyping on 692,367 markers. “Loci passing the genome-wide significance threshold for association were subject to conditional analysis to identify any independent associations,” they added.

A total of 1223 patients with AAD and 4096 controls were included in the final analyses. Current Scandinavian reports estimate “a prevalence between 13 and 22 cases per 100,000 inhabitants, which corresponded to a single nucleotide polymorphism (SNP) heritability rate for AAD between 34 and 40%,” meaning “35–41% of the heritability estimated in twins (h2 ≈ 0.97) is explained by the SNPs covered in this GWAS,” authors explained.

Analyses revealed 9 risk loci exceeding the genome-wide significance (P ≤ 5×10−8). Of these:

  • The human leukocyte antigen (HLA) region stood our as the major risk locus (top SNP rs3998178; P < 10−179)
  • AAD was associated with variants in or adjacent to PTPN22CTLA4LPPBACH2SH2B3SIGLEC5UBASH3A, and AIRE
  • PTPN22CTLA4, HLA, AIRE, and BACH2 were previously implicated in AAD and LPPSH2B3SIGLEC5, and UBASH3A were novel

As mutations in AIRE cause the monogenic disease autoimmune polyglandular syndrome type 1 (APS-1), of which AAD is a major component, authors conducted further investigations into this associated peak, revealing:

  1. By conditioning on the top AIRE SNP rs74203920, a second independent signal in AIRE (rs2075876, Pcond. < 7.8 × 10−14), which was not in linkage disequilibrium (LD) with the covariate rs74203920 (r2 < 0.01), was found
  2. Of these 2 independent associations, the top SNP rs74203920 was a novel association, whereas rs2075876 had been investigated previously
  3. rs2075876 was in LD with the coding SNP rs1800520 (r2 = 0.83)
  4. The risk allele rs74203920-T was uncommon in Swedish and Norwegian controls (2%) and in the non-Finnish European population (1.4% GnomAD v2.1.1), but was strongly enriched among cases with AAD (MAF = 6.5%)

In an additional examination of the HLA association, researchers found “7 independent alleles and amino acids associated with AAD at the genome-wide significance level (P value <5 × 10−8).”

As autoimmune diseases co-occur in affected individuals and share some genetic risk factors, investigators analyzed the overlap of risk loci with diseases and traits previously investigated in other GWAS. Results showed AAD displayed a significant overlap of genetic risk loci with its most common comorbidities including inflammatory bowel diseases and organ-specific autoimmune diseases.

However, the strongest of the novel risk alleles discovered (the lead SNP in AIRE [rs74203920]) has not been linked to other autoimmune diseases in GWAS.

“The results point to the complex network of antigen presentation and immunomodulation that underlie autoimmune disease development,” authors wrote.

“Dysregulation of antigen presentation in the setting of negative selection in the thymus may be one of the factors that makes AAD exceptional among organ-specific autoimmune diseases, and the pathways identified should be explored in the development of preventive treatment strategies,” they concluded.


Eriksson D, Røyrvik EC, Aranda-Guillén M, et al. GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility. Nat Commun. Published online February 11, 2021. doi:10.1038/s41467-021-21015-8