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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 melanocytes1, with epidemiological association with other autoimmune diseases2. 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.

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Figure 1: Genome-wide meta-analysis results.
Figure 2: Bioinformatic functional interaction network analysis of the proteins encoded by all positional candidate genes at all confirmed and suggestive vitiligo candidate loci.
Figure 3: Concordant associations for vitiligo and other autoimmune and inflammatory diseases.
Figure 4: Enrichment estimates for functional annotation categories.

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Acknowledgements

We thank the thousands of patients with vitiligo and normal control individuals around the world who participated in this study. We thank the Center for Inherited Disease Research (CIDR) for genotyping. This work used the Janus supercomputer, which is supported by the National Science Foundation (award CNS-0821794), the University of Colorado Boulder, the University of Colorado Denver, and the National Center for Atmospheric Research. The Janus supercomputer is operated by the University of Colorado Boulder. This work was supported by grants R01AR045584, R01AR056292, X01HG007484, and P30AR057212 from the US National Institutes of Health and by institutional research funding IUT20-46 from the Estonian Ministry of Education and Research.

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Authors and Affiliations

Authors

Contributions

Y.J., G.A., and D.Y. performed statistical analyses. J.S. managed computer databases, software, and genotype data. T.M.F., S.B., G.A., and K.M.B. managed DNA samples and contributed to experimental procedures. P.J.H. managed subject coordination. S.A.B., A.H., A.L., R.M.L., A.W., J.P.W.v.d.V., N.v.G., J.L., D.C.B., A.T., K.E., E.H.K., D.J.G., A.P.W., S.K., E.P., K.K., M.K., M.R.W., W.T.M., A.O., S.M., R.C., M.P., N.B.S., M.O., Y.V., I.K., M.B., H.W.L., I.H., L.Z., and Q.-S.M. provided subject samples and phenotype information. S.A.S., P.R.F., and R.A.S. conceived, oversaw, and managed all aspects of the study. R.A.S. wrote the first draft of the manuscript. All authors contributed to the final manuscript.

Corresponding author

Correspondence to Richard A Spritz.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Significant colocalizations of vitiligo GWAS association signals and cis-eQTLs in purified blood monocytes.

(a) CASP7. (b) FARP2STK25. (c) FBXO45NRROS. (d) OCA2HERC2. (e) RERE. (f) RNASET2FGFR1OPCCR6. (g) TICAM1. (h) ZC3H7BTEF. For specific probes, see Supplementary Table 4

Supplementary information

Supplementary Figure 1

Significant colocalizations of vitiligo GWAS association signals and cis-eQTLs in purified blood monocytes. (PDF 405 kb)

Supplementary Table 1

Most significant variant at all significant and suggestive vitiligo susceptibility loci. (XLSX 26 kb)

Supplementary Table 2

Annotation of independent association signals at vitiligo-associated loci for ENCODE immune-related and melanocyte-related data sets. (XLSX 161 kb)

Supplementary Table 3

Significant PrediXcan results after Bonferroni correction (P < 4.33 × 10–6). (XLSX 22 kb)

Supplementary Table 4

Vitiligo GWAS and monocyte eQTL colocalization significant and suggestive results. (XLSX 15 kb)

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Jin, Y., Andersen, G., Yorgov, D. et al. Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants. Nat Genet 48, 1418–1424 (2016). https://doi.org/10.1038/ng.3680

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