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 WolffGerhard 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, Angela M. Christiano

Research output: Contribution to journalArticlepeer-review

192 Scopus citations

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.

Original languageEnglish (US)
Article number5966
JournalNature communications
Volume6
DOIs
StatePublished - Jan 22 2015

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© 2015 Macmillan Publishers Limited. All rights reserved.

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