title: Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.
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.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.|Department of Epidemiology, Columbia University, NY, NY.
authors.forename: Lynn
authors.initials: L
authors.lastname: Petukhova
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Androniki
authors.initials: A
authors.lastname: Menelaou
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Redler
authors.affiliation: German Center for Neurodegenerative Diseases, Bonn, Germany.|Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University Bonn, Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heilmann
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.
authors.forename: Tarek
authors.initials: T
authors.lastname: Yamany
authors.affiliation: Department of Dermatology, MD Anderson Cancer Center, Houston,TX.
authors.forename: Madeliene
authors.initials: M
authors.lastname: Duvic
authors.affiliation: Department of Dermatology, University of Minnesota, Minneapolis, MN.
authors.forename: Maria
authors.initials: M
authors.lastname: Hordinsky
authors.affiliation: Department of Dermatology, University of Colorado, Denver, CO, US.
authors.forename: David
authors.initials: D
authors.lastname: Norris
authors.affiliation: Department of Dermatology, University of California, San Francisco, San Francisco CA.
authors.forename: Vera H
authors.initials: VH
authors.lastname: Price
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.
authors.forename: Julian
authors.initials: J
authors.lastname: Mackay-Wiggan
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.
authors.forename: Annemieke
authors.initials: A
authors.lastname: de Jong
authors.affiliation: Department of Genetics & Development, Columbia University, NY, NY.
authors.forename: Gina M
authors.initials: GM
authors.lastname: DeStefano
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, University Duisburg-Essen, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Blume-Peytavi
authors.affiliation: Department of Dermatology, University of Munich, Munich, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Wolff
authors.affiliation: Dermatological Practice, Hair and Nail, Wesseling, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Lutz
authors.affiliation: Dermatological Practice, Paderborn, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kruse
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.affiliation: Community and Family Medicine and Genetics, Dartmouth College, Hanover, NH, US.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset NY.
authors.forename: Annette
authors.initials: A
authors.lastname: Lee
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset NY.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Bettina
authors.initials: B
authors.lastname: Blaumeiser
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.|Department of Medicine Columbia University, NY, NY.
authors.forename: Raphael
authors.initials: R
authors.lastname: Clynes
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PIW
authors.lastname: de Bakker
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life&Brain Center, University Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Department of Dermatology, Columbia University, NY, NY.|Department of Genetics & Development, Columbia University, NY, NY.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000506:Alopecia Areata / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000067698:Ataxin-2 / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011487:Protein Conformation; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012867:Skin / Q000378:metabolism
chemical_list: C000593752:ATXN2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000067698:Ataxin-2; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D006680:HLA Antigens; D047908:Intracellular Signaling Peptides and Proteins; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C490778:SH2B3 protein, human