GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility

Nat Commun. 2021 Feb 11;12(1):959. doi: 10.1038/s41467-021-21015-8.

Abstract

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Addison Disease / genetics*
  • Basic-Leucine Zipper Transcription Factors / genetics
  • CTLA-4 Antigen / genetics
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Models, Molecular
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Risk

Substances

  • BACH2 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22