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Nat Commun. 2015 Jan 22;6:5966. doi: 10.1038/ncomms6966.

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

Author information

1
Institute of Human Genetics, University of Bonn, Bonn, Germany.
2
Department of Dermatology, Columbia University, NY, NY.
3
Department of Epidemiology, Columbia University, NY, NY.
4
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
5
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
6
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
7
German Center for Neurodegenerative Diseases, Bonn, Germany.
8
Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn.
9
Department of Genomics, Life&Brain Center, University Bonn, Bonn, Germany.
10
Department of Dermatology, MD Anderson Cancer Center, Houston,TX.
11
Department of Dermatology, University of Minnesota, Minneapolis, MN.
12
Department of Dermatology, University of Colorado, Denver, CO, US.
13
Department of Dermatology, University of California, San Francisco, San Francisco CA.
14
Department of Genetics & Development, Columbia University, NY, NY.
15
Institute of Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen, Essen, Germany.
16
Department of Dermatology, University of Münster, Münster, Germany.
17
Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
18
Department of Dermatology, University of Munich, Munich, Germany.
19
Dermatological Practice, Hair and Nail, Wesseling, Germany.
20
Dermatological Practice, Paderborn, Germany.
21
Community and Family Medicine and Genetics, Dartmouth College, Hanover, NH, US.
22
The Feinstein Institute for Medical Research, Manhasset NY.
23
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
24
Department of Medicine Columbia University, NY, NY.
25
Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
#
Contributed equally

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.

PMID:
25608926
PMCID:
PMC4451186
DOI:
10.1038/ncomms6966
[Indexed for MEDLINE]
Free PMC Article

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