Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata

Abstract

Alopecia areata (AA) is a genetically determined, immune-mediated disorder of the hair follicle that affects 1%-2% of the U.S. population. It is defined by a spectrum of severity that ranges from patchy localized hair loss on the scalp to the complete absence of hair everywhere on the body. In an effort to define the genetic basis of AA, we performed a genomewide search for linkage in 20 families with AA consisting of 102 affected and 118 unaffected individuals from the United States and Israel. Our analysis revealed evidence of at least four susceptibility loci on chromosomes 6, 10, 16 and 18, by use of several different statistical approaches. Fine-mapping analysis with additional families yielded a maximum multipoint LOD score of 3.93 on chromosome 18, a two-point affected sib pair (ASP) LOD score of 3.11 on chromosome 16, several ASP LOD scores >2.00 on chromosome 6q, and a haplotype-based relative risk LOD of 2.00 on chromosome 6p (in the major histocompatibility complex locus). Our findings confirm previous studies of association of the human leukocyte antigen locus with human AA, as well as the C3H-HeJ mouse model for AA. Interestingly, the major loci on chromosomes 16 and 18 coincide with loci for psoriasis reported elsewhere. These results suggest that these regions may harbor gene(s) involved in a number of different skin and hair disorders.

Figure 1.

Clinical presentation of AA. A and B, AA appearing as well-circumscribed patches of hair loss on the scalp. C, Alopecia universalis, the complete form of AA, which leads to absence of all hair on the body. D, AA with selective loss of pigmented hair, with a patch of white hair left behind. E, Representative examples of pedigree structures of the families with AA. Participating family members are indicated by an asterisk (*).

Figure 2.

Proportion of top 25 scores on a given chromosome for analysis of pedigrees with AA by use of each of the four test statistics.

Figure 3.

Results of the fine-mapping study for chromosome 6. A, Region 52.33–54.71 cM. B, Region 134.2–150.93 cM.

Figure 4.

Results of the fine-mapping study for chromosome 10. A, Region 41.19–51.42 cM. B, Region 124.64–147.86 cM.

Figure 5.

Results of the fine-mapping study for chromosome 16

Figure 6.

Results of the fine-mapping study for chromosome 18

Figure 7.

Comparison of chromosome 18 results with published studies.^, Boxes represent regions that showed linkage. Asterisks (*) indicate marker loci with the highest linkage scores. HSS = hereditary hypotrichosis simplex; PSOR = psoriasis.