Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C

Recent genome scans have established the presence of a major psoriasis-susc eptibility locus in the human leukocyte antigen (HLA) complex on chromosome 6p21.3. To narrow the interval for candidate gene testing, we performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physica lly mapped microsatellite markers spanning the major histocompatibility com plex (MHC). As detected by use of the transmission/disequilibrium test (TDT ), individual markers yielded significant linkage disequilibrium across mos t of the MHC. However, the strongest evidence for marker-trait disequilibri um was found in an similar to 300-kb region extending from the MICA gene to the corneodesmosin gene. Maximum-likelihood haplotypes were constructed ac ross the entire MHC in the original sample and across a 1.2-Mb region of th e central MHC in an expanded sample containing 139 additional families. Sho rt (two- to five-marker) haplotypes were subjected to the TDT using a "movi ng-window" strategy that reduced the variability of TDT P values relative t o the single-locus results. Furthermore, the expanded sample yielded a shar p peak of evidence for linkage disequilibrium that spanned similar to 170 k b and that was centered 100 kb telomeric to HLA-C. The 1.2-Mb interval was further dissected by means of recombinant ancestral haplotype analysis. Thi s analysis identified risk haplotype 1 (RH1), which is a GO-kb fragment of ancestral haplotype 57.1, on all identifiable HLA risk haplotypes. One of t hese haplotypes exhibits significant linkage disequilibrium with psoriasis but does not carry Cw6, which is the HLA allele most strongly associated wi th the disease. These results demonstrate that RH1 is highly likely to carr y the disease allele at PSORS1, and they exclude HLA-C and corneodesmosin w ith a high degree of confidence.