Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease.
Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.



To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.



We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10-15, MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.



Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, Sweden.
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0000-0001-5473-3312
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Eriksson
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Bianchi
Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Landegren
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Nordin
Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Dalin
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Mathioudaki
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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Eriksson
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Hultin-Rosenberg
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Dahlqvist
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Zetterqvist
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Karlsson
Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Hallgren
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Farias
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Murén
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Ahlgren
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Lobell
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
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Andersson
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Tandre
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
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Dahlqvist
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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Söderkvist
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Rönnblom
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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Hulting
Department of Endocrinology, Department of Medical and Health Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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Wahlberg
Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Ekwall
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
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Dahlqvist
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Meadows
Department of Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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Bensing
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Lindblad-Toh
Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Endocrinology, Metabolism and Diabetes Karolinska University Hospital, Stockholm, Sweden.|Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Kämpe
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
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Pielberg
D000224:Addison Disease / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D017421:Sequence Analysis; D055815:Young Adult
C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D000949:Histocompatibility Antigens Class II
Addison Disease; BACH2 protein; genetic; genetic association studies; genetic predisposition to disease; human; polymorphism