title: Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.
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.
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Andersen
authors.affiliation: Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, Colorado, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yorgov
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Ferrara
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Songtao
authors.initials: S
authors.lastname: Ben
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Brownson
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Paulene J
authors.initials: PJ
authors.lastname: Holland
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Dermatology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Stanca A
authors.initials: SA
authors.lastname: Birlea
authors.affiliation: CytoAnalytics, Denver, Colorado, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Siebert
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Lienert
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Nanja
authors.initials: N
authors.lastname: van Geel
authors.affiliation: Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Lambert
authors.affiliation: Netherlands Institute for Pigment Disorders, Department of Dermatology, Academic Medical Centre University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Luiten
authors.affiliation: Netherlands Institute for Pigment Disorders, Department of Dermatology, Academic Medical Centre University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Wolkerstorfer
authors.affiliation: Netherlands Institute for Pigment Disorders, Department of Dermatology, Academic Medical Centre University of Amsterdam, Amsterdam, the Netherlands.|Department of Dermatology, Medical Centre Haaglanden, The Hague, the Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Wietze van der Veen
authors.affiliation: Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.affiliation: Centre de Référence des Maladies Rares de la Peau, Department of Dermatology, Hôpital St.-André, Bordeaux, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Taïeb
authors.affiliation: Centre de Référence des Maladies Rares de la Peau, Department of Dermatology, Hôpital St.-André, Bordeaux, France.
authors.forename: Khaled
authors.initials: K
authors.lastname: Ezzedine
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: E Helen
authors.initials: EH
authors.lastname: Kemp
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gawkrodger
authors.affiliation: Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Weetman
authors.affiliation: Department of Pathophysiology, University of Tartu, Tartu, Estonia.
authors.forename: Sulev
authors.identifier: 0000-0001-6087-6643
authors.initials: S
authors.lastname: Kõks
authors.affiliation: Department of Pathophysiology, University of Tartu, Tartu, Estonia.
authors.forename: Ele
authors.initials: E
authors.lastname: Prans
authors.affiliation: Department of Dermatology, University of Tartu, Tartu, Estonia.
authors.forename: Külli
authors.initials: K
authors.lastname: Kingo
authors.affiliation: Department of Dermatology, University of Tartu, Tartu, Estonia.
authors.forename: Maire
authors.initials: M
authors.lastname: Karelson
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wallace
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Wayne T
authors.initials: WT
authors.lastname: McCormack
authors.affiliation: Lumiderm, Madrid, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Overbeck
authors.affiliation: Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.affiliation: Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Colucci
authors.affiliation: Laboratorio Fisiopatologia Cutanea, Istituto Dermatologico San Gallicano, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Picardo
authors.affiliation: Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, New York, USA.|Pediatric and Adolescent Dermatology, St. Luke's-Roosevelt Hospital Center, New York, New York, USA.
authors.forename: Nanette B
authors.initials: NB
authors.lastname: Silverberg
authors.affiliation: International Vitiligo Center, Uppsala, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Olsson
authors.affiliation: Vitiligo Research Foundation, New York, New York, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Valle
authors.affiliation: Vitiligo Research Foundation, New York, New York, USA.|Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Igor
authors.initials: I
authors.lastname: Korobko
authors.affiliation: Department of Dermatology, University of Münster, Münster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Henry W
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Iltefat
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authors.affiliation: Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Fain
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, Colorado, USA.|Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Santorico
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA.|Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics; D040641:Quantitative Trait Loci; D018570:Risk Assessment; D014820:Vitiligo / Q000235:genetics*