Genotyping the NPF Biobank for Psoriasis Susceptibility Genes

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DESCRIPTION (provided by applicant): Genotyping the NPF Biobank for Psoriasis Susceptibility Genes This application addresses broad Challenge Area (08) Genomics and Specific Challenge Area: 08-AR-101 Genotyping of Existing Cohorts in Rheumatic, Skin, and Musculoskeletal Diseases. Psoriasis is a common, immunologically-mediated disease of the skin and joints, with a strong genetic basis. In an effort to identify psoriasis susceptibility genes, we participated in the Collaborative Association Study of Psoriasis (CASP) with support from the Genetic Association Information Network (GAIN). Together with collaborators from Washington University at St. Louis and the University of Utah, we tested 438,670 single- nucleotide polymorphisms (SNPs) in 1,409 European ancestry psoriasis cases and 1,436 controls in a genome-wide association study (GWAS). Twenty-one SNPs representing 18 loci showing promising evidence of association in the GWAS were followed-up in 5,048 psoriasis cases and 5,041 controls. The loci with confirmed association encode HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R and IL12B), two genes that act downstream of TNF-¿ and regulate NF-¿B signaling (TNIP1 and TNFAIP3), and a set of genes involved in the modulation of Th2 immune responses (IL4 and IL13). These results support the hypothesis that immunoregulatory genes are associated with psoriasis, and support the hypothesis that many more psoriasis susceptibility genes remain to be identified. We are currently carrying out a much more extensive follow-up study of over 8,000 SNPs in 3,263 cases, 2781 controls, and 832 family members. This analysis will fine-map PSORS1 and the other confirmed psoriasis loci, and will test ~5,000 additional promising genetic signals from the initial GWAS. The National Psoriasis Foundation (NPF) has established the Victor Henschel Biobank for the purpose of confirming psoriasis susceptibility loci. The goal of this ARRA Challenge Grant application is to utilize this outstanding NPF clinical and genetic resource, together with additional samples provided by the U-M Psoriasis Genetics Laboratory, to identify additional susceptibility genes for psoriasis and psoriatic arthritis, and to make the results rapidly and widely available for analysis by other scientists. In pursuit of this goal, we propose the following specific aims: 1. To type at least 1,500 new cases and 1,500 new controls from the NPF Victor Henschel Biobank and the U-M Psoriasis Genetics Laboratory for 7,600 SNPs identified as promising from the CASP deep follow-up study. 2. To deposit detailed clinical phenotypes as well as the results of the genotyping to be performed in Aim 1 in the database of Genotypes and Phenotypes (dbGAP) as soon as quality control checks are complete, and to analyze these data for association with psoriasis separately and together with existing datasets. 1 Psoriasis is a common inflammatory disease of the skin and joints, affecting over 4 million Americans. Its cause is not well understood. Identification of genes that increase risk of psoriasis will help us unlock the secrets of this troubling disease, and identify targets for more specific and effective therapy.