Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

被引：226

作者：

Jin, Ying ^{[1
,2
]}

Andersen, Genevieve ^{[1
]}

Yorgov, Daniel ^{[3
]}

Ferrara, Tracey M. ^{[1
]}

Ben, Songtao ^{[1
]}

Brownson, Kelly M. ^{[1
]}

Holland, Paulene J. ^{[1
]}

Birlea, Stanca A. ^{[1
,4
]}

Siebert, Janet ^{[5
]}

Hartmann, Anke ^{[6
]}

Lienert, Anne ^{[6
]}

van Geel, Nanja ^{[7
]}

Lambert, Jo ^{[7
]}

Luiten, Rosalie M. ^{[8
]}

Wolkerstorfer, Albert ^{[8
]}

van der Veen, J. P. Wietze ^{[8
,9
]}

Bennett, Dorothy C. ^{[10
]}

Taieb, Alain ^{[11
]}

Ezzedine, Khaled ^{[11
]}

Kemp, E. Helen ^{[12
]}

Gawkrodger, David J. ^{[12
]}

Weetman, Anthony P. ^{[12
]}

Koks, Sulev ^{[13
]}

Prans, Ele ^{[13
]}

Kingo, Kulli ^{[14
]}

Karelson, Maire ^{[14
]}

Wallace, Margaret R. ^{[15
]}

McCormack, Wayne T. ^{[16
]}

Overbeck, Andreas ^{[17
]}

Moretti, Silvia ^{[18
]}

Colucci, Roberta ^{[18
]}

Picardo, Mauro ^{[19
]}

Silverberg, Nanette B. ^{[20
,21
]}

Olsson, Mats ^{[22
]}

Valle, Yan ^{[23
]}

Korobko, Igor ^{[23
,24
]}

Boehm, Markus ^{[25
]}

Lim, Henry W. ^{[26
]}

Hamzavi, Iltefat ^{[26
]}

Zhou, Li ^{[26
]}

Mi, Qing-Sheng ^{[26
]}

Fain, Pamela R. ^{[1
,2
]}

Santorico, Stephanie A. ^{[1
,3
,27
]}

Spritz, Richard A. ^{[1
,2
]}

机构：

[1] Univ Colorado, Sch Med, Human Med Genet & Genom Program, Aurora, CO 80045 USA

[2] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA

[3] Univ Colorado, Dept Math & Stat Sci, Denver, CO 80202 USA

[4] Univ Colorado, Sch Med, Dept Dermatol, Aurora, CO USA

[5] CytoAnalytics, Denver, CO USA

[6] Univ Hosp Erlangen, Dept Dermatol, Erlangen, Germany

[7] Ghent Univ Hosp, Dept Dermatol, Ghent, Belgium

[8] Univ Amsterdam, Acad Med Ctr, Dept Dermatol, Netherlands Inst Pigment Disorders, Amsterdam, Netherlands

[9] Med Ctr Haaglanden, Dept Dermatol, The Hague, Netherlands

[10] St Georges Univ London, Mol & Clin Sci Res Inst, London, England

[11] Hop St Andre, Dept Dermatol, Ctr Reference Malad Rares Peau, Bordeaux, France

[12] Univ Sheffield, Dept Oncol & Metab, Sheffield, S Yorkshire, England

[13] Univ Tartu, Dept Pathophysiol, Tartu, Estonia

[14] Univ Tartu, Dept Dermatol, Tartu, Estonia

[15] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL USA

[16] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL USA

[17] Lumiderm, Madrid, Spain

[18] Univ Florence, Dept Surg & Translat Med, Sect Dermatol, Florence, Italy

[19] Ist Dermatol S Maria & S Gallicano, Lab Fisiopatol Cutanea, Rome, Italy

[20] Columbia Univ Coll Phys & Surg, Dept Dermatol, New York, NY 10032 USA

[21] St Lukes Roosevelt Hosp, Pediat & Adolescent Dermatol, New York, NY USA

[22] Int Vitiligo Ctr, Uppsala, Sweden

[23] Vitiligo Res Fdn, New York, NY USA

[24] Russian Acad Sci, Inst Gene Biol, Moscow, Russia

[25] Univ Munster, Dept Dermatol, Munster, Germany

[26] Henry Ford Hosp, Dept Dermatol, Detroit, MI 48202 USA

[27] Univ Colorado, Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 11期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; NONMELANOMA SKIN-CANCER; GENERALIZED VITILIGO; SUSCEPTIBILITY LOCI; COMMON VARIANTS; PARTITIONING HERITABILITY; RHEUMATOID-ARTHRITIS; HAN CHINESE; GRANZYME-B; IN-VIVO;

D O I：

10.1038/ng.3680

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytesl, with epidemiological association with other autoimmune diseases(2). In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

引用

页码：1418 / 1424

页数：7

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