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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 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.

SUBMITTER: Jin Y

PROVIDER: S-EPMC5120758 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Jin Ying Y Andersen Genevieve G Yorgov Daniel D Ferrara Tracey M TM Ben Songtao S Brownson Kelly M KM Holland Paulene J PJ Birlea Stanca A SA Siebert Janet J Hartmann Anke A Lienert Anne A van Geel Nanja N Lambert Jo J Luiten Rosalie M RM Wolkerstorfer Albert A Wietze van der Veen J P JP Bennett Dorothy C DC Taïeb Alain A Ezzedine Khaled K Kemp E Helen EH Gawkrodger David J DJ Weetman Anthony P AP Kõks Sulev S Prans Ele E Kingo Külli K Karelson Maire M Wallace Margaret R MR McCormack Wayne T WT Overbeck Andreas A Moretti Silvia S Colucci Roberta R Picardo Mauro M Silverberg Nanette B NB Olsson Mats M Valle Yan Y Korobko Igor I Böhm Markus M Lim Henry W HW Hamzavi Iltefat I Zhou Li L Mi Qing-Sheng QS Fain Pamela R PR Santorico Stephanie A SA Spritz Richard A RA

Nature genetics 20161010 11

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, follow ...[more]

PMID: 27723757

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Project description:Vitiligo is a chronic skin condition lack of melanocytes. However, researches on the aetiology and pathogenesis of vitiligo are still under debate. This study aimed to explore the key genes and pathways associated with occurrence and development of vitiligo.Weighted gene coexpression network analysis (WGCNA) was applied to reanalyze the gene expression dataset GSE65127 systematically. Functional enrichments of these modules were carried out at gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set variation analysis (GSVA), and gene set enrichment analysis (GSEA). Then, a map of regulatory network was delineated according to pivot analysis and drug prediction. In addition, hub genes and crucial pathways were validated by an independent dataset GSE75819. The expressions of hub genes in modules were also tested by quantitative real-time polymerase chain reaction (qRT-PCR).Eight coexpressed modules were identified by WGCNA based on 5794 differentially expressed genes of vitiligo. Three modules were found to be significantly correlated with Lesional, Peri-Lesional, and Non-Lesional, respectively. The persistent maladjusted genes included 269 upregulated genes and 82 downregulated genes. The enrichments showed module genes were implicated in immune response, p53 signaling pathway, etc. According to GSEA and GSVA, dysregulated pathways were activated incessantly from Non-Lesional to Peri-Lesional and then to Lesional, 4 of which were verified by an independent dataset GSE75819. Finally, 42 transcription factors and 228 drugs were spotted. Focusing on the persistent maladjusted genes, a map of regulatory network was delineated. Hub genes (CACTIN, DCTN1, GPR143, HADH, MRPL47, NKTR, NUF2) and transcription factors (ITGAV, SYK, PDPK1) were validated by an independent dataset GSE75819. In addition, hub genes (CACTIN, DCTN1, GPR143, MRPL47, NKTR) were also confirmed by qRT-PCR.The present study, at least, might provide an integrated and in-depth insight for exploring the underlying mechanism of vitiligo and predicting potential diagnostic biomarkers and therapeutic targets.

Project description:Fungal diseases, drought, pre-harvest sprouting (PHS) and other biotic and abiotic stresses have seriously affected the quality and yield in wheat production. Identifying related genes/loci in released cultivars/lines can provide reference information and theoretical basis for wheat improvement. Yannong series wheat cultivars/lines have distinctive characteristics in wheat cultivars and play an important role in genetic improvement and production of Chinese wheat production system. To dissect their genetic basis of the stress-resistant traits, in this study, 23 representative Yannong series wheat cultivars/lines were tested by 58 molecular markers for 40 genes related to adaptability, disease resistance and stress tolerance to clarify the genetic composition of the key loci. The results showed that most of the tested wheat accessions carried dwarfing genes RhtB1b/RhtD1b/Rht8 and recessive vernalization genes vrn-A1/vrn-B1/vrn-D1/vrn-B3. It was also consistent with the phenotypic traits of tested Yannong series wheat which were dwarf and winter or semi winter wheat. In addition, the overall level of seedling powdery mildew resistance in 23 Yannong wheat cultivars/lines was moderate or inadequate. Eleven accessions carried none of the tested Pm genes and twelve accessions carried Pm2, Pm6, Pm42 and Pm52 singly or in combination. Then, 23 wheat cultivars/lines were also tested by 17 diagnostic markers for 14 Yr genes. The results showed that 16 wheat cultivars/lines were likely to carry one or more of tested Yr genes, whereas Yannong 15, Yannong 17, Yannong 23, Yannong 24, Yannong 377, Yannong 572 and Yannong 999 carried none of the tested Yr genes. Moreover, in our study, nine markers for four genes related to drought tolerance and PHS were used to evaluate the stress tolerance of the 23 wheat cultivars/lines. The results indicated that all 23 wheat cultivars/lines carried drought resistance genes Ta-Dreb1/TaCRT-D, indicating that they had the drought resistance to the extent. Except for Yannong 30, Yannong 377, Yannong 390, Yannong 745 and Yannong 1766, other wheat cultivars/lines carried one to three elite PHS-resistant alleles Vp-1Bc/Vp-1Bf/TaAFP-1Bb.

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

Publications

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

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