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

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102 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

Bibliographical note

Funding Information:
We are deeply indebted to the many patients and their family members who participated in this study. We are thankful to Drs Lawrence Shapiro and Tatyana Gindin for guidance on the structural effects of HLA associations. We thank Spandon V. Shah, Holly Jiang, Matthew Ding and Steven Chiu for their assistance and contributions in isolating the immune cells by FACS and Jane E. Cerise for her bioinformatic expertise. We are most grateful for the support of the National Alopecia Areata Foundation for funding the initial studies, and Ms Vicki Kalabokes and her staff at NAAF for their efforts on our behalf. The US patient cohort was collected and maintained by the National Alopecia Areata Registry (N01-AR62279) (to M.D.). Some controls were drawn from the Heinz Nixdorf Recall Study cohort, which was established with the support of the Heinz Nixdorf Foundation. R.C.B. and M.M.N. are members, T.B. is an associate member, of the DFG-funded Excellence Cluster ImmunoSensation. R.C.B. is a recipient of a Heisenberg Professorship of the German Research Foundation (DFG). This work was supported in part by the DFG grant BE 2346/5-1, as well as by local funding (BONFOR) to R.C.B., Vernieuwingsimpuls VIDI Award from the Netherlands Organization for Scientific Research for project 016.126.354 to P.I.W.d.B., and USPHS NIH/NIAMS grants R01AR52579 and R01AR56016 (to A.M.C.).

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