In the past decade, genome-wide association studies (GWAS) and genetic linkage studies have been central to the elucidation of the pathogenesis of AA. Compared to GWAS of other autoimmune and immune-mediated diseases, the “hits” obtained from the AA GWAS have yielded a higher number of meaningful candidate genes that have shed light on the mechanisms of disease in AA [
3], providing new therapeutic targets.
In our first GWAS for AA, which included 1054 AA patients from a comprehensive registry (National Alopecia Areata Registry) in North America, we identified eight regions of the genome that were significantly associated with AA [
4]. Like other autoimmune conditions, the human leukocyte antigen (HLA) locus was significantly represented in the AA GWAS, supporting previous candidate gene association studies [
5,
6]. Interestingly, the second highest peak uncovered in our GWAS, and confirmed in other cohorts, mapped to the
ULBP6/ULBP3 gene locus on chromosome 6q. Functional studies confirmed that ULBP3 was aberrantly upregulated as a danger signal on the hair follicles of AA patients [
4,
7], which contributed to the collapse of immune privilege, and the recruitment of cytotoxic CD8
+ NKG2D
+ T cells to carry out destruction of the hair follicle. We subsequently showed that this subset of T cells was both necessary and sufficient for the development of AA. Meta-analysis of GWAS studies in AA was conducted on the combined North American and European AA cohorts [
8], and confirmed the significance of these susceptibility loci, as well as identifying several new loci.
Applying pathway and network analyses (e.g., Gene Ontology term enrichment and proteomic interactions) to the GWAS data has also uncovered sets of genes that contribute to pathogenic processes. This type of analysis grouped AA with other autoimmune diseases like type 1 diabetes, rheumatoid arthritis (RA), and celiac disease. Pathways that are implicated in the pathogenesis of this group of autoimmune diseases include antigen processing and presentation, co-stimulatory pathways, and JAK-STAT signaling [
9]. These associations led to a re-analysis of the underlying immunopathogenesis of AA, and to a consideration of employing new therapies that target these pathways specifically.