Psoriasis (Ps) is a common chronic inflammatory skin disease affecting approximately 2-3% of individuals of European ancestry. 10-40% of the time it is accompanied by a disabling psoriatic arthritis (PsA). Other co-morbidities include metabolic syndrome and an increased risk for cardiovascular disease and stroke. Genome-wide association studies have identified over 20 predisposing loci, but account for less than 20% of disease heritability. We recently used a combination of linkage analysis and NexGen sequencing to identify mutations in caspase recruitment domain protein 14 (CARD14) in two families with highly penetrant forms of Ps and PsA, thereby successfully identifying the PSORS2 locus on human chromosome 17q25. Screening of over 5,000 cases and controls revealed additional rare variants in CARD14 and an excess of variants in cases versus controls. We also identified a single severe psoriasis case with a de-novo mutation in CARD14. Ps/PsA associated mutations enhanced NF- kB activation and altered the transcriptome of keratinocytes, leading to the production of chemokines and other psoriasis-associated inflammatory markers. In the current application we will extend our genetic analyses of CARD14 in an extended cohort of Ps/PsA patients and controls. We will also perform exome capture or whole genome sequencing on cases with sporadic and familial forms of Ps and PsA to screen for additional genes with rare highly penetrant variants predisposing to disease. By targeting cases or families with both Ps and PsA we hope to reduce possible genetic heterogeneity. Genes will be prioritized for follow up on the basis of known biological roles/pathway altered in Ps/PsA or if they are enriched for deleterious variants. Additional variants in these genes will be identified with targeted capture (4 genes per year). Those with additional variants in cases versus controls will be genotyped in a larger cohort of >5,000 cases and 5,000 controls. Statistical analyzes will then be performed to examine the contribution of rare variants in specifi genes to Ps and PsA susceptibility. Functional studies of novel variants will be performed to complement the genetic studies. By identifying rare highly penetrant mutations leading to these diseases, we will increase our understanding of disease pathogenesis and identify novel therapeutic targets lying within pathways altered in Ps/PsA.