TY - JOUR
T1 - Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci
AU - Betz, Regina C.
AU - Petukhova, Lynn
AU - Ripke, Stephan
AU - Huang, Hailiang
AU - Menelaou, Androniki
AU - Redler, Silke
AU - Becker, Tim
AU - Heilmann, Stefanie
AU - Yamany, Tarek
AU - Duvic, Madeliene
AU - Hordinsky, Maria
AU - Norris, David
AU - Price, Vera H.
AU - MacKay-Wiggan, Julian
AU - De Jong, Annemieke
AU - DeStefano, Gina M.
AU - Moebus, Susanne
AU - Böhm, Markus
AU - Blume-Peytavi, Ulrike
AU - Wolff, Hans
AU - Lutz, Gerhard
AU - Kruse, Roland
AU - Bian, Li
AU - Amos, Christopher I.
AU - Lee, Annette
AU - Gregersen, Peter K.
AU - Blaumeiser, Bettina
AU - Altshuler, David
AU - Clynes, Raphael
AU - De Bakker, Paul I W
AU - Nöthen, Markus M.
AU - Daly, Mark J.
AU - Christiano, Angela M.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/1/22
Y1 - 2015/1/22
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms6966
DO - 10.1038/ncomms6966
M3 - Article
C2 - 25608926
AN - SCOPUS:84938251791
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 5966
ER -
