Unraveling the molecular causes of alopecia areata (AA): whole-genome sequencing in patients with AA plus other autoimmune diseases

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Alopecia areata (AA) is a common autoimmune-mediated disorder in humans with an estimated lifetime risk of approximately 2 %. Episodes of hair loss usually begin with the development of isolated hairless patches that may spread centrifugally and progress to complete hair loss over the entire body. If symptoms persist for a long time, the prognosis is unfavorable with regard to therapeutic responsiveness or spontaneous remission. The psychological impact on affected individuals is severe, including increased rates of clinically relevant anxiety and depression. AA is generally thought to be a multifactorial disorder involving both environmental and genetic factors. Genome-wide association studies (GWAS) of AA have so far identified 14 susceptibility loci, demonstrating the polygenic nature of the disease. Little attention has been paid in the field of AA genetics to the fact that AA can also occur as an associated clinical feature of a number of monogenic syndromes that severely compromise the immune system and lead to immunodeficiency and/or autoimmunity. These syndromes are caused by mutations in key immune genes. Particularly intriguing is the incomplete penetrance of some of these mutations and/or the variable expression of clinical phenotypes. These observations and the fact that a subset of AA patients (more than 400 patients out of our total cohort of 2.500) are affected by additional autoimmune diseases -we refer to this as AAPAD (alopecia areata plus other autoimmune disease(s))- may open a whole new avenue in the field of AA genetics. We hypothesize that AAPAD cases are due to specific genetic causes and are intermediate between the very rare autoimmune syndromes and the multifactorial AA cases, representing a continuous spectrum of autoimmunity with AA as the common feature. Therefore, the aim of the present proposal is to detect rare variants in the coding and noncoding genome with moderate to large effects by whole-genome sequencing (WGS) in our AAPAD group. Briefly, a total of 400 AAPAD patients will be subjected to WGS and then screened for candidate mutations by use of diverse bioinformatic analyses. As next step, we aim to perform targeted sequencing of the most promising 10 genes emerging from WGS data in the rest of the AA cohort with help of single molecule Molecular Inversion Probe (smMIP) technology. 2-3 genes/variants gaining robust evidence for causality from WGS and targeted sequencing data will be functionally characterized by in vitro experiments. The identification of such rare variants and the mechanistic concepts derived from them would i) provide important insights into the etiology of AA and general autoimmunity, paving the way for the development of novel therapeutics and ii) could significantly impact the way we clinically diagnose AA in the future.