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

Daniel Eriksson(Uppsala University), Ellen C. Røyrvik(University of Bergen), Maribel Aranda‐Guillén(Karolinska Institutet), Amund Holte Berger(Haukeland University Hospital), Nils Landegren(Uppsala University), Haydeé Artaza(University of Bergen), Åsa Hallgren(Karolinska Institutet), Marianne Aardal Grytaas(Haukeland University Hospital), Sara S. Strom(Karolinska University Hospital), Eirik Bratland(Haukeland University Hospital), Ileana Ruxandra Botusan(Karolinska University Hospital), Bergithe E Oftedal(University of Bergen), Lars Breivik(Haukeland University Hospital), Marc Vaudel(University of Bergen), Øyvind Helgeland(Norwegian Institute of Public Health), Alberto Falorni(University of Perugia), Anders Palmstrøm Jørgensen(Oslo University Hospital), Anna‐Lena Hulting(Karolinska Institutet), Johan Svartberg(University Hospital of North Norway), Olov Ekwall(University of Gothenburg), Kristian J. Fougner(St Olav's University Hospital), Jeanette Wahlberg(Linköping University), Bjørn Gunnar Nedrebø(Privatsykehuset Haugesund), Per Dahlqvist(Umeå University), The Norwegian Addison Registry Study Group(University of Bergen), Helge Ræder(Haraldsplass Diakonale Sykehus), Nevena Jovanovic(Haraldsplass Diakonale Sykehus), Sigfrid Christine Reisegg(Helse Førde), Geir Hølleland(Stavanger University Hospital), Siri Carlsen(University of Oslo), Tore Julsrud Berg(Lovisenberg Diakonale Sykehus), Jan Bertil Eggesbø(Diakonhjemmet Hospital), Thomas Svendsen(Oslo University Hospital), Kari Lima(Akershus University Hospital), Ingrid Nermoen(Vestre Viken Hospital Trust), Rolf Whitfield(Vestre Viken Hospital Trust), Stina Therese Sollid(Vestre Viken Hospital Trust), Dagfinn Aarskog(Vestre Viken Hospital Trust), Elin Korsgaard(Vestre Viken Hospital Trust), Solveig Sæta(Innlandet Hospital Trust), Trine Finnes(Innlandet Hospital Trust), Susanna F Valland(Innlandet Hospital Trust), Caroline Fossum(Akershus University Hospital), Eli Brevik(Østfold Hospital Trust), Ragnar Bekkhus Moe(Østfold Hospital Trust), Margrethe Svendsen(Sykehuset i Vestfold), Aleksandra Dębowska(Telemark Hospital), Petya Milova(Sørlandet Hospital Arendal), Synnøve Emblem Holte(Sørlandet Sykehus), Aneta Eva Tomkowicz(Levanger Hospital), Dag Eirik Sørmo(Namsos Hospital), Anders Svare(Ålesund Hospital), Marthe Landsverk Rensvik(Volda University College), Randi Revheim(Molde Hospital), T. Haug(Kristiansund Sykehus), Ivar Blix(Nordland Hospital Trust), Lars Petter Jensen(Karolinska Institutet), The Swedish Addison Registry Study Group(Karolinska Institutet), Anna‐Karin Åkerman(Lund University), Anna‐Lena Hulting(Karolinska Institutet), Bengt Lindberg(Skåne University Hospital), Berit Kriström(University of Gothenburg), Erik Waldenström(Karolinska Institutet), Gudmundur Johannsson(Linköping University), Jakob Skov(Linköping University), Jeanette Wahlberg(Linköping University), Karel Duchén(Lund University), Magnus Isaksson(Karolinska Institutet), Maria Elfving(Karolinska Institutet), Maria Halldin Stenlid(Karolinska University Hospital), Ola Nilsson(University of Gothenburg), Olle Kämpe(Karolinska University Hospital), Olov Ekwall(University of Gothenburg), Per Dahlqvist(Karolinska Institutet), Ragnhildur Bergthorsdottir(Karolinska Institutet), Ricard Nergårdh(Karolinska Institutet), Sigríður Björnsdóttir(Umeå University), Sophie Bensing(Karolinska University Hospital), Tommy Olsson(University of Bergen), Per M. Knappskog(Haukeland University Hospital), Anette S. B. Wolff(Haukeland University Hospital), Sophie Bensing(Karolinska University Hospital), Stefan Johansson(Haukeland University Hospital), Olle Kämpe(Karolinska University Hospital), Eystein S. Husebye(Haukeland University Hospital)
Nature Communications
February 11, 2021
10.1038/s41467-021-21015-8
Cited by 82Open Access
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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 ).

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