Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

Regina C. Betz, Lynn Petukhova, Stephan Ripke, Hailiang Huang, Androniki Menelaou, Silke Redler, Tim Becker, Stefanie Heilmann, Tarek Yamany, Madeliene Duvic, Maria Hordinsky, David Norris, Vera H. Price, Julian Mackay-Wiggan, Annemieke de Jong, Gina M. DeStefano, Susanne Moebus, Markus Böhm, Ulrike Blume-Peytavi, Hans Wolff, Gerhard Lutz, Roland Kruse, Li Bian, Christopher I. Amos, Annette Lee, Peter K. Gregersen, Bettina Blaumeiser, David Altshuler, Raphael Clynes, Paul I. W. de Bakker, Markus M. Nöthen, Mark J. Daly and Angela M. Christiano ()
Additional contact information
Regina C. Betz: Institute of Human Genetics, University of Bonn
Lynn Petukhova: Columbia University
Stephan Ripke: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School
Hailiang Huang: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School
Androniki Menelaou: University Medical Center Utrecht
Silke Redler: Institute of Human Genetics, University of Bonn
Tim Becker: German Center for Neurodegenerative Diseases
Stefanie Heilmann: Institute of Human Genetics, University of Bonn
Tarek Yamany: Columbia University
Madeliene Duvic: MD Anderson Cancer Center
Maria Hordinsky: University of Minnesota
David Norris: University of Colorado
Vera H. Price: University of California, San Francisco
Julian Mackay-Wiggan: Columbia University
Annemieke de Jong: Columbia University
Gina M. DeStefano: Columbia University
Susanne Moebus: Institute of Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen
Markus Böhm: University of Münster
Ulrike Blume-Peytavi: Clinical Research Center for Hair and Skin Science, Charité-Universitätsmedizin Berlin
Hans Wolff: University of Munich
Gerhard Lutz: Dermatological Practice, Hair and Nail
Roland Kruse: Dermatological Practice
Li Bian: Columbia University
Christopher I. Amos: Community and Family Medicine and Genetics, Dartmouth College
Annette Lee: The Feinstein Institute for Medical Research
Peter K. Gregersen: The Feinstein Institute for Medical Research
Bettina Blaumeiser: University of Antwerp
David Altshuler: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School
Raphael Clynes: Columbia University
Paul I. W. de Bakker: University Medical Center Utrecht
Markus M. Nöthen: Institute of Human Genetics, University of Bonn
Mark J. Daly: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School
Angela M. Christiano: Columbia University

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: Abstract Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.

Date: 2015
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DOI: 10.1038/ncomms6966

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