Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci

The pathogenesis of all forms of psoriasis remains obscure. Segregation ana lysis and twin studies together with ethnic differences in disease frequenc y all point to an underlying genetic susceptibility to psoriasis, which is both complex and Likely to reflect the action of a number of genes. We perf ormed a genome wide analysis using a total of 271 polymorphic autosomal mar kers on 284 sib relative pairs identified within 158 independent families. We detected evidence for linkage at 6p21 (PSORS1) with a non-parametric lin kage score (NPL)=4.7, p=2 x 10(-6) and at chromosome 1p (NPL=3.6, p=1.9 x 1 0(-4)) in all families studied. Significant excess (p=0.004) paternal allel e sharing was detected for markers spanning the PSORS1 locus. A further thr ee regions reached NPL scores of 2 or greater, including a region at chromo some 7 (NPL. 2.1), for which linkage for a number of autoimmune disorders h as been reported. Partitioning of the data set according to allele sharing at 6p21 (PSORS1) favoured linkage to chromosomes 2p (NPL 2.09) and 14q (NPL 2.0), both regions implicated in previous independent genome scans, and su ggests evidence for epistasis between PSORS1 and genes at other genomic loc ations. This study has provided linkage evidence in favour of a novel susce ptibility locus for psoriasis and provides evidence of the complex mechanis ms underlying the genetic predisposition to this common skin disease.