GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
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Published:2021-02-11
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Eriksson DanielORCID, , Røyrvik Ellen ChristineORCID, Aranda-Guillén MaribelORCID, Berger Amund HolteORCID, Landegren Nils, Artaza HaydeeORCID, Hallgren Åsa, Grytaas Marianne AardalORCID, Ström Sara, Bratland Eirik, Botusan Ileana Ruxandra, Oftedal Bergithe Eikeland, Breivik LarsORCID, Vaudel MarcORCID, Helgeland ØyvindORCID, Falorni Alberto, Jørgensen Anders PalmstrømORCID, Hulting Anna-Lena, Svartberg Johan, Ekwall OlovORCID, Fougner Kristian Johan, Wahlberg Jeanette, Nedrebø Bjørn Gunnar, Dahlqvist PerORCID, Knappskog Per Morten, Wolff Anette Susanne Bøe, Bensing SophieORCID, Johansson StefanORCID, Kämpe OlleORCID, Husebye Eystein SverreORCID,
Abstract
AbstractAutoimmune 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).
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference75 articles.
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