Journal Article

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

Aranda-Guillén, Maribel, Bensing, Sophie, Røyrvik, Ellen Christine, Landegren, Nils, Jørgensen, Anders Palmstrøm, Berger, Amund Holte, Vaudel, Marc, Ekwall, Olov, Wolff, Anette Susanne Bøe, Kämpe, Olle, Helgeland, Øyvind, Knappskog, Per Morten, Breivik, Lars, Hulting, Anna-Lena, Ström, Sara, Fougner, Kristian Johan, Falorni, Alberto, Johansson, Stefan, Wahlberg, Jeanette, Grytaas, Marianne Aardal, Bratland, Eirik, Botusan, Ileana Ruxandra, Dahlqvist, Per, Hallgren, Åsa, Nedrebø, Bjørn Gunnar, Husebye, Eystein Sverre, Oftedal, Bergithe Eikeland, Artaza, Haydee, Eriksson, Daniel, Svartberg, Johan

2021

Overview

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 ( h 2 ). Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator ( AIRE ).

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/43 / 631/208/248/144 / 692/163/2743/1279 / Addison Disease - genetics / Adrenal cortex / AIRE protein / Autoimmune diseases / Basic-Leucine Zipper Transcription Factors - genetics / CTLA-4 Antigen - genetics / CTLA-4 protein / Disease / Endocrine disorders / Endocrinology and Diabetes / Endokrinologi och diabetes / Female / Genome-wide association studies / Genome-Wide Association Study / Genomes / Heredity / Heritability / Histocompatibility antigen HLA / Humanities and Social Sciences / Humans / Immunological tolerance / Immunology / Loci / Lymphocytes / Male / Models, Molecular / multidisciplinary / Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics / Protein-tyrosine-phosphatase / Proteins / Risk / Science / Science & Technology - Other Topics / Science (multidisciplinary) / Zinc finger proteins