Psoriasis is a common, chronic inflammatory skin disease that affects approximately 2% of the N. European population. 10-40% of the time it is accompanied by psoriatic arthritis. Psoriasis is a complex disease with a number of predisposing variants and environmental triggers. A comprehensive understanding of the genetics of psoriasis is important for understanding its pathogenesis and is unlikely to be revealed by an analysis of single candidate genes. One major determinant is a locus within the HLA class I region (PSORS1) and over nineteen non-HLA loci have been reported following genome-wide linkage scans. The penetrance of associated alleles within HLA is ~10% and it is believed that epistasis with some of these non HLA alleles is required for disease development. There may also be loci that are entirely HLA-dependent. Linkage analyses have had limited success in identifying susceptibility loci for psoriasis, and the common variant-common disease hypothesis suggests that a global genome association screen may be far more successful at identifying susceptibility variants. We intend to exploit a high throughput global screen for associated SNPs, identified from the HapMap project. 317,000 SNPs from the Illumina Hap300K array will be typed in 500 cases and matched controls of European origin, previously evaluated for underlying substructure. Follow-up studies of 3840 SNPs will be performed in 1,000 newly ascertained cases and controls. 250 of the most highly associated SNPs will be typed in 750 newly ascertained trios. 5-15 regions harboring potential psoriasis susceptibility genes will be targeted for disease gene/variant identification. Once variants are identified they, and their predisposing genes will be evaluated in our complete set of >1250 cases/controls and 1250 trios, representative of all cases in our collection, regardless of ethnicity. This will permit a preliminary analysis of gene-gene and gene-environment interactions.
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