NEW YORK (GenomeWeb) – Through a genome-wide association study, an international team of researchers has linked nearly two dozen new loci to the skin condition vitiligo.
Vitiligo is an autoimmune disorder in which melanocytes are destroyed, causing skin color to be lost in blotches. Previous linkage studies and GWAS associated 27 genetic loci with vitiligo susceptibility, and researchers led by the University of Colorado School of Medicine's Richard Spritz have now expanded upon these studies to link a further 23 loci to the condition. In addition, they found that a number of these susceptibility loci are involved in other autoimmune disorders and encode immune and apoptotic regulators as well as melanocyte regulators, as they reported today in Nature Genetics.
"This study doubles the number of known genes involved in risk for vitiligo," Spritz said in a statement.
For their study, Spritz and his colleagues added to the number of population controls in their two previous GWAS — bringing them to1,381 cases and 14,518 controls and to 413 cases and 5,209 controls — and added a third GWAS of 1,059 cases and 17,678 controls. They also combined these studies to perform a meta-analysis and turned to a further 1,827 cases and 2,181 controls for replication.
Through this, the researchers identified 23 loci linked to vitiligo, two of which had been suggested in previous work. Together with previously known loci, the 48 total loci account for 17.4 percent of vitiligo heritability, the researchers calculated. When they uncovered additional independent associations at eight loci and the major histocompatibility complex, that estimate increased to 22.5 percent.
Spritz and his colleagues also screened the vitiligo-linked loci to search for functional relationships. They noted an enrichment of Gene Ontology terms related to immune response, the regulation of stimuli response, and more. Similarly, pathway analysis using the STRING database of protein-protein interactions uncovered a potential interaction network with numerous proteins involved in immune regulation, apoptosis, and melanocyte function.
Of the 23 new vitiligo susceptibility loci, about a dozen encode proteins involved in immune regulation, while six regulate apoptosis. One, ASIP, regulates melanocytes, and another, IRF4, is an important transcription factor in immune cells and in melanocytes.
The researchers further noted that some of these vitiligo-associated genes encode proteins that interact with one another. For example, BCL2L11 and BAD bind to promote apoptosis and ASIP binds MC1R to downregulate brown-black eumelanin production.
From their series of GWAS, the researchers also uncovered an inverse relationship between vitiligo and malignant melanoma risk genes. This, they added, suggests that vitiligo susceptibility might be due to overly active immune surveillance against melanoma.
Vitiligo is also linked to other autoimmune disorders, like autoimmune thyroid disease, rheumatoid arthritis, and lupus. When Spritz and his colleagues searched through the National Human Genome Research Institute–European Bioinformatics Institute GWAS catalog and PubMed, they found links between the 23 new vitiligo susceptibility loci and other autoimmune diseases: FASLG is linked with celiac disease and Crohn's disease, PTPRC with ulcerative colitis, and BCL2L111 with primary sclerosing cholangitis.
The researchers also reported that a number of the loci they uncovered corresponded to expression quantitative trait loci, and many of those involved gene expression regulation in immune cells, melanocytes, or both.
"One of the purposes of the genome project was to give us the tools to do more complicated disease analysis," Spritz added. "What's emerging in general for complex diseases is that it is changes in gene regulation rather than gene structure that are causes."