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

View Article: PubMed Central - PubMed

ABSTRACT

Vitiligo is an autoimmune disease in which depigmented skin results from destruction of melanocytes1, with epidemiologic association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1, GWAS2), we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We carried out a third GWAS (GWAS3) in EUR 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 loci and 7 suggestive loci, most encoding immune and apoptotic regulators, some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some corresponding to eQTL at these loci. Together, the identified genes provide a framework for vitiligo genetic architecture and pathobiology, highlight relationships to other autoimmune diseases and melanoma, and offer potential targets for treatment.

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Bioinformatic functional interaction network analysis of proteins encoded by all positional candidate genes at all confirmed and suggestive vitiligo candidate loci. As a first step, unsupervised functional interaction network analysis was carried out using STRING v10.011, considering each protein as a node and permitting ≤ 5 second-order interactions to maximize connectivity. Nodes that shared no edges with other nodes were then excluded from the network. Edge colors are per STRING: teal, interactions from curated databases; purple, experimentally determined interactions; green, gene neighborhood; blue, databases; red, gene fusions; dark blue, gene co-occurrence; pale green, text-mining; black, co-expression; lavender, protein homology. Note that SMEK2 is an alternative name for PPP4R3B.
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Figure 2: Bioinformatic functional interaction network analysis of proteins encoded by all positional candidate genes at all confirmed and suggestive vitiligo candidate loci. As a first step, unsupervised functional interaction network analysis was carried out using STRING v10.011, considering each protein as a node and permitting ≤ 5 second-order interactions to maximize connectivity. Nodes that shared no edges with other nodes were then excluded from the network. Edge colors are per STRING: teal, interactions from curated databases; purple, experimentally determined interactions; green, gene neighborhood; blue, databases; red, gene fusions; dark blue, gene co-occurrence; pale green, text-mining; black, co-expression; lavender, protein homology. Note that SMEK2 is an alternative name for PPP4R3B.

Mentions: To screen for functional relationships among proteins encoded at the 48 confirmed vitiligo-associated loci, we included all genes under the association peaks at these loci in unsupervised pathway analyses using g:PROFILER9, PANTHER10, and STRING11. PANTHER and gPROFILER identified an enriched network of BioGRID interactions, most significant for the GO categories immune response, immune system process, positive regulation of response to stimulus, positive regulation of biological process, and regulation of response to stimulus. STRING identified a large potential interaction network (Fig. 2), with a predominance of proteins involved in immunoregulation, T-cell receptor repertoire, apoptosis, antigen processing and presentation, and melanocyte function.


Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants
Bioinformatic functional interaction network analysis of proteins encoded by all positional candidate genes at all confirmed and suggestive vitiligo candidate loci. As a first step, unsupervised functional interaction network analysis was carried out using STRING v10.011, considering each protein as a node and permitting ≤ 5 second-order interactions to maximize connectivity. Nodes that shared no edges with other nodes were then excluded from the network. Edge colors are per STRING: teal, interactions from curated databases; purple, experimentally determined interactions; green, gene neighborhood; blue, databases; red, gene fusions; dark blue, gene co-occurrence; pale green, text-mining; black, co-expression; lavender, protein homology. Note that SMEK2 is an alternative name for PPP4R3B.
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Related In: Results  -  Collection

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Figure 2: Bioinformatic functional interaction network analysis of proteins encoded by all positional candidate genes at all confirmed and suggestive vitiligo candidate loci. As a first step, unsupervised functional interaction network analysis was carried out using STRING v10.011, considering each protein as a node and permitting ≤ 5 second-order interactions to maximize connectivity. Nodes that shared no edges with other nodes were then excluded from the network. Edge colors are per STRING: teal, interactions from curated databases; purple, experimentally determined interactions; green, gene neighborhood; blue, databases; red, gene fusions; dark blue, gene co-occurrence; pale green, text-mining; black, co-expression; lavender, protein homology. Note that SMEK2 is an alternative name for PPP4R3B.
Mentions: To screen for functional relationships among proteins encoded at the 48 confirmed vitiligo-associated loci, we included all genes under the association peaks at these loci in unsupervised pathway analyses using g:PROFILER9, PANTHER10, and STRING11. PANTHER and gPROFILER identified an enriched network of BioGRID interactions, most significant for the GO categories immune response, immune system process, positive regulation of response to stimulus, positive regulation of biological process, and regulation of response to stimulus. STRING identified a large potential interaction network (Fig. 2), with a predominance of proteins involved in immunoregulation, T-cell receptor repertoire, apoptosis, antigen processing and presentation, and melanocyte function.

View Article: PubMed Central - PubMed

ABSTRACT

Vitiligo is an autoimmune disease in which depigmented skin results from destruction of melanocytes1, with epidemiologic association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1, GWAS2), we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We carried out a third GWAS (GWAS3) in EUR 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 loci and 7 suggestive loci, most encoding immune and apoptotic regulators, some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some corresponding to eQTL at these loci. Together, the identified genes provide a framework for vitiligo genetic architecture and pathobiology, highlight relationships to other autoimmune diseases and melanoma, and offer potential targets for treatment.

No MeSH data available.


Related in: MedlinePlus