GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
Daniel Eriksson, Ellen C. Røyrvik, Maribel Aranda‐Guillén, Amund Holte Berger, Nils Landegren, Haydeé Artaza, Åsa Hallgren, Marianne Aardal Grytaas, Sara S. Strom, Eirik Bratland, Ileana Ruxandra Botusan, Bergithe E Oftedal, Lars Breivik, Marc Vaudel, Øyvind Helgeland, Alberto Falorni, Anders Palmstrøm Jørgensen, Anna‐Lena Hulting, Johan Svartberg, Olov Ekwall, Kristian J. Fougner, Jeanette Wahlberg, Bjørn Gunnar Nedrebø, Per Dahlqvist, The Norwegian Addison Registry Study Group, Helge Ræder, Nevena Jovanovic, Sigfrid Christine Reisegg, Geir Hølleland, Siri Carlsen, Tore Julsrud Berg, Jan Bertil Eggesbø, Thomas Svendsen, Kari Lima, Ingrid Nermoen, Rolf Whitfield, Stina Therese Sollid, Dagfinn Aarskog, Elin Korsgaard, Solveig Sæta, Trine Finnes, Susanna F Valland, Caroline Fossum, Eli Brevik, Ragnar Bekkhus Moe, Margrethe Svendsen, Aleksandra Dębowska, Petya Milova, Synnøve Emblem Holte, Aneta Eva Tomkowicz, Dag Eirik Sørmo, Anders Svare, Marthe Landsverk Rensvik, Randi Revheim, T. Haug, Ivar Blix, Lars Petter Jensen, The Swedish Addison Registry Study Group, Anna‐Karin Åkerman, Anna‐Lena Hulting, Bengt Lindberg, Berit Kriström, Erik Waldenström, Gudmundur Johannsson, Jakob Skov, Jeanette Wahlberg, Karel Duchén, Magnus Isaksson, Maria Elfving, Maria Halldin Stenlid, Ola Nilsson, Olle Kämpe, Olov Ekwall, Per Dahlqvist, Ragnhildur Bergthorsdottir, Ricard Nergårdh, Sigríður Björnsdóttir, Sophie Bensing, Tommy Olsson, Per M. Knappskog, Anette S. B. Wolff, Sophie Bensing, Stefan Johansson, Olle Kämpe, Eystein S. Husebye
Abstract
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 ( h 2 ).