The Genetic Architecture of Alopecia Areata

Alopecia areata (AA) is the most prevalent autoimmune disease in the US. With An estimated lifetime risk of 1.7%, it affects both genders with similar frequencies and people of all ages. AA affects more individuals than most other autoimmune diseases combined, and yet despite its prevalence, there is an enormous unmet medical need, in part due to the dearth of information about the underlying pathogenesis. In AA, autoimmunity arises against the hair follicles in the skin, which causes hair loss associated with an aberrant accumulation of immune-response cells around the affected hair follicles. Evidence supporting a genetic basis for AA stems from multiple lines of research, including increased risk of disease in first degree relatives, twin studies, and more recently, our initial family-based linkage study and genome wide association study (GWAS) in a cohort of unrelated individuals. Importantly, our GWAS identified a set of 16 statistically independent risk haplotypes across 8 loci, implicating specific genes that increase risk of AA, all of which have been validated. Genome wide genetic studies can provide critical insight into disease mechanisms, especially when little is known about the underlying causes of disease. In this study, I use complementary gene mapping methods, performing one study in a cohort of families and a second study in a cohort of unrelated cases and controls. Using these two approaches, I obtain new evidence about the genetic influences on AA. Our family cohort contains statistically significant evidence for linkage at a new locus, on chromosome 2q36.1-q37.3 (LOD=4.17) and family-based tests of association implicate 47 genes. I then conducted a GWAS that expanded our initial cohort with the addition of 800 cases and obtained statistically significant evidence for a new locus at chromosome 16p13.13 (p=4.6x10-7). This region has been implicated in several other autoimmune diseases and contains several genes that are known to be involved with immune processes. Taken together, these two studies demonstrate the presence of both rare and common variants are contributing to AA etiology and support emerging evidence that suggests the genetic architecture of common complex diseases involves both rare and common variants.