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

Ying Jin; Genevieve Andersen; Daniel Yorgov; Tracey M Ferrara; Songtao Ben; Kelly M Brownson; Paulene J Holland; Stanca A Birlea; Janet Siebert; Anke Hartmann; Anne Lienert; Nanja van Geel; Jo Lambert; Rosalie M Luiten; Albert Wolkerstorfer; J P Wietze van der Veen; Dorothy C Bennett; Alain Taïeb; Khaled Ezzedine; E Helen Kemp; David J Gawkrodger; Anthony P Weetman; Sulev Kõks; Ele Prans; Külli Kingo; Maire Karelson; Margaret R Wallace; Wayne T McCormack; Andreas Overbeck; Silvia Moretti; Roberta Colucci; Mauro Picardo; Nanette B Silverberg; Mats Olsson; Yan Valle; Igor Korobko; Markus Böhm; Henry W Lim; Iltefat Hamzavi; Li Zhou; Qing-Sheng Mi; Pamela R Fain; Stephanie A Santorico; Richard A Spritz

doi:10.1038/ng.3680

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

Nat Genet. 2016 Nov;48(11):1418-1424. doi: 10.1038/ng.3680. Epub 2016 Oct 10.

Authors

Ying Jin^{1

2}, Genevieve Andersen¹, Daniel Yorgov³, Tracey M Ferrara¹, Songtao Ben¹, Kelly M Brownson¹, Paulene J Holland¹, Stanca A Birlea^{1

4}, Janet Siebert⁵, Anke Hartmann⁶, Anne Lienert⁶, Nanja van Geel⁷, Jo Lambert⁷, Rosalie M Luiten⁸, Albert Wolkerstorfer⁸, J P Wietze van der Veen^{8

9}, Dorothy C Bennett¹⁰, Alain Taïeb¹¹, Khaled Ezzedine¹¹, E Helen Kemp¹², David J Gawkrodger¹², Anthony P Weetman¹², Sulev Kõks¹³, Ele Prans¹³, Külli Kingo¹⁴, Maire Karelson¹⁴, Margaret R Wallace¹⁵, Wayne T McCormack¹⁶, Andreas Overbeck¹⁷, Silvia Moretti¹⁸, Roberta Colucci¹⁸, Mauro Picardo¹⁹, Nanette B Silverberg^{20

21}, Mats Olsson²², Yan Valle²³, Igor Korobko^{23

24}, Markus Böhm²⁵, Henry W Lim²⁶, Iltefat Hamzavi²⁶, Li Zhou²⁶, Qing-Sheng Mi²⁶, Pamela R Fain^{1

2}, Stephanie A Santorico^{1

3

27}, Richard A Spritz^{1

2}

Affiliations

¹ Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
² Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
³ Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, Colorado, USA.
⁴ Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁵ CytoAnalytics, Denver, Colorado, USA.
⁶ Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
⁷ Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
⁸ Netherlands Institute for Pigment Disorders, Department of Dermatology, Academic Medical Centre University of Amsterdam, Amsterdam, the Netherlands.
⁹ Department of Dermatology, Medical Centre Haaglanden, The Hague, the Netherlands.
¹⁰ Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.
¹¹ Centre de Référence des Maladies Rares de la Peau, Department of Dermatology, Hôpital St.-André, Bordeaux, France.
¹² Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
¹³ Department of Pathophysiology, University of Tartu, Tartu, Estonia.
¹⁴ Department of Dermatology, University of Tartu, Tartu, Estonia.
¹⁵ Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA.
¹⁶ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
¹⁷ Lumiderm, Madrid, Spain.
¹⁸ Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
¹⁹ Laboratorio Fisiopatologia Cutanea, Istituto Dermatologico San Gallicano, Rome, Italy.
²⁰ Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, New York, USA.
²¹ Pediatric and Adolescent Dermatology, St. Luke's-Roosevelt Hospital Center, New York, New York, USA.
²² International Vitiligo Center, Uppsala, Sweden.
²³ Vitiligo Research Foundation, New York, New York, USA.
²⁴ Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
²⁵ Department of Dermatology, University of Münster, Münster, Germany.
²⁶ Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA.
²⁷ Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA.

PMID: 27723757
PMCID: PMC5120758
DOI: 10.1038/ng.3680

Abstract

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. 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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Autoimmune Diseases / genetics*
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study
Genotype
Humans
Male
Melanoma / genetics
Quantitative Trait Loci
Risk Assessment
Vitiligo / genetics*

Abstract

Publication types

MeSH terms

Grants and funding