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

被引：206

作者：

Betz, Regina C. ^{[1
]}

Petukhova, Lynn ^{[2
,3
]}

Ripke, Stephan ^{[4
,5
,6
]}

Huang, Hailiang ^{[4
,5
,6
]}

Menelaou, Androniki ^{[7
]}

Redler, Silke ^{[1
]}

Becker, Tim ^{[8
,9
]}

Heilmann, Stefanie ^{[1
,10
]}

Yamany, Tarek ^{[2
]}

Duvic, Madeliene ^{[11
]}

Hordinsky, Maria ^{[12
]}

Norris, David ^{[13
]}

Price, Vera H. ^{[14
]}

Mackay-Wiggan, Julian ^{[2
]}

de Jong, Annemieke ^{[2
]}

DeStefano, Gina M. ^{[15
]}

Moebus, Susanne ^{[16
]}

Boehm, Markus ^{[17
]}

Blume-Peytavi, Ulrike ^{[18
]}

Wolff, Hans ^{[19
]}

Lutz, Gerhard

Kruse, Roland

Bian, Li ^{[2
]}

Amos, Christopher I. ^{[20
]}

Lee, Annette ^{[21
]}

Gregersen, Peter K. ^{[21
]}

Blaumeiser, Bettina ^{[22
]}

Altshuler, David ^{[4
,5
,6
]}

Clynes, Raphael ^{[2
,23
]}

de Bakker, Paul I. W. ^{[7
,24
]}

Noethen, Markus M. ^{[1
,10
]}

Daly, Mark J. ^{[4
,5
,6
]}

Christiano, Angela M. ^{[2
,15
]}

机构：

[1] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany

[2] Columbia Univ, Dept Dermatol, New York, NY 10032 USA

[3] Columbia Univ, Dept Epidemiol, New York, NY 10032 USA

[4] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[5] Harvard Univ, Sch Med, Boston, MA 02114 USA

[6] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02114 USA

[7] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CG Utrecht, Netherlands

[8] German Ctr Neurodegenerat Dis, D-53175 Bonn, Germany

[9] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-53127 Bonn, Germany

[10] Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany

[11] Univ Texas MD Anderson Canc Ctr, Dept Dermatol, Houston, TX 77030 USA

[12] Univ Minnesota, Dept Dermatol, Minneapolis, MN 55455 USA

[13] Univ Colorado, Dept Dermatol, Denver, CO 80204 USA

[14] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94110 USA

[15] Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA

[16] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, D-45122 Essen, Germany

[17] Univ Munster, Dept Dermatol, D-48149 Munster, Germany

[18] Charite, Clin Res Ctr Hair & Skin Sci, Dept Dermatol & Allergy, D-10117 Berlin, Germany

[19] Univ Munich, Dept Dermatol, D-80337 Munich, Germany

[20] Dartmouth Coll, Hanover, NH 03755 USA

[21] Feinstein Inst Med Res, Manhasset, NY 11030 USA

[22] Univ Antwerp, Dept Med Genet, BE-2650 Antwerp, Belgium

[23] Columbia Univ, Dept Med, New York, NY 10032 USA

[24] Univ Med Ctr Utrecht, Dept Epidemiol, NL-3584 CG Utrecht, Netherlands

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

LATENT TGF-BETA; RISK LOCUS; GARP; AUTOPHAGOSOMES; EXPRESSION; RATIONALE; APOPTOSIS; PROTEINS; DISEASE; SURFACE;

D O I：

10.1038/ncomms6966

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：8

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