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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR052579-01A1
Application #
7099110
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (12))
Program Officer
Baker, Carl
Project Start
2006-05-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
1
Fiscal Year
2006
Total Cost
$380,221
Indirect Cost
Name
Columbia University (N.Y.)
Department
Dermatology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Betz, Regina C; Petukhova, Lynn; Ripke, Stephan et al. (2015) Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci. Nat Commun 6:5966
Jabbari, Ali; Petukhova, Lynn; Cabral, Rita M et al. (2013) Genetic basis of alopecia areata: a roadmap for translational research. Dermatol Clin 31:109-17
Petukhova, Lynn; Duvic, Madeleine; Hordinsky, Maria et al. (2010) Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature 466:113-7
Martinez-Mir, Amalia; Zlotogorski, Abraham; Gordon, Derek et al. (2007) Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata. Am J Hum Genet 80:316-28
Ahn, Kwangmi; Haynes, Chad; Kim, Wonkuk et al. (2007) The effects of SNP genotyping errors on the power of the Cochran-Armitage linear trend test for case/control association studies. Ann Hum Genet 71:249-61