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

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).

Primary Ovarian Insufficiency in Women With Addison’s Disease

“…We also excluded 22 women with known autoimmune polyendocrine syndrome type-1, leaving 461 women with AAD who all had autoantibodies against 21OH. The registry contains information on age at AAD diagnosis, age at menopause and other autoimmune manifestations autoantibody profiles, and genome-wide single nucleotide polymorphism (SNP) data ( 18 , 19 ). POI was diagnosed based on standard clinical and biochemical criteria (1) oligo/amenorrhea, and (2) an elevated FSH level in menopausal reference range ( 1 ).…”

“…Recently generated whole-genome genotype data were retrieved for 432 women with AAD from ROAS, of whom 44 had POI ( 18 ). Due to the low number of patients with POI, we selected 104 candidate genes based on the Genomics England list of POI genes and risk loci for AAD ( 18 , 21 ) (see supplementary table for details ( 22 )).…”

“…Recently generated whole-genome genotype data were retrieved for 432 women with AAD from ROAS, of whom 44 had POI ( 18 ). Due to the low number of patients with POI, we selected 104 candidate genes based on the Genomics England list of POI genes and risk loci for AAD ( 18 , 21 ) (see supplementary table for details ( 22 )). For each candidate gene, the longest gene transcript region (defined by the University of California Santa Cruz Gene Browser) was selected, and all SNPs within these regions were extracted from quality-controlled imputed genotype data (for details on input data and imputation, see ( 18 )).…”

“…Due to the low number of patients with POI, we selected 104 candidate genes based on the Genomics England list of POI genes and risk loci for AAD ( 18 , 21 ) (see supplementary table for details ( 22 )). For each candidate gene, the longest gene transcript region (defined by the University of California Santa Cruz Gene Browser) was selected, and all SNPs within these regions were extracted from quality-controlled imputed genotype data (for details on input data and imputation, see ( 18 )). The variant sets were pruned for triallelic markers and markers in linkage disequilibrium , and a set-based association test was performed in Plink ( 23 ).…”

“…Spontaneous POI has been linked to multiple genetic loci involved in oogenesis, folliculogenesis, DNA damage repair, homologous recombination, and meiosis ( 16 , 17 ). To date, there are limited data on any potential genetic basis of autoimmune POI, but a recent genome-wide association study on AAD can perhaps provide hints to the pathogenesis ( 18 ).…”