Alopecia areata (AA) affects approximately 4.6 million individuals in the United States alone, including males and females of all ages and ethnic groups. Despite its high incidence, its pathomechanism is largely unknown. Although the presence of genetic components conferring susceptibility for developing AA is now widely accepted, this has not translated into studies investigating the genetic basis of AA. Up to now, genetic studies have been limited to association analyses, which suggest that a permissive HLA status may potentiate the development of the AA phenotype. A systematic screen for identifying the primary genetic mechanisms underlying this disorder has never before been undertaken. Some authors have openly advocated in favor of conducting genome-wide linkage analyses in AA, irrespective of the challenges inherent to complex diseases:"... the extent to which this disorder causes morbidity and its incidence warrant investigation for the genes underlying alopecia areata (Green and Sinclair 2000). It is now generally accepted that AA fits the paradigm of a complex or multifactorial trait, in which a combination of genetic and environmental factors combine to result in the final phenotype. In this application, we outline further evidence supporting a polygenic model of inheritance in AA, such as clustering in families, no clear pattern of Mendelian inheritance, a Gaussian distribution of phenotypes, high population prevalence, concordance in twin studies, and an increased risk to first-degree relatives. Importantly, the genomics and computational technology for the analysis of such diseases has vastly improved in recent years. There are currently a number of examples of complex diseases of the skin, such as atopic dermatitis and psoriasis, in which genetic studies have been successfully undertaken that substantiate the timeliness of this approach. We have initiated a comprehensive genetic analysis of AA, as outlined in this proposal. Importantly, we provide evidence for suggestive linkage at four independent loci in the human genome. These include loci on chromosomes 6, 10, 16 and 18. In the context of this proposal, we will perform fine-mapping and gene identification in AA, and go on to demonstrate the association of pathogenic variants in candidate genes with the inheritance of disease. We anticipate these studies will provide a foundation for understanding the interactions of these genes with each other and with other variables such as the immune system.