Human Molecular Genetics Advance Access originally published online on March 25, 2008
Human Molecular Genetics 2008 17(13):1938-1945; doi:10.1093/hmg/ddn091
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Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene
1 Division of Genetics and Molecular Medicine 2 Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK 3 Institute of Human Genetics, University of Erlangen-Nurnberg, Erlangen, Germany 4 Myriad Genetics, Salt Lake City, UT, USA 5 arc Epidemiology Unit 6 Dermatological Sciences, University of Manchester, Manchester, UK 7 Department of Dermatology, University of Glasgow, Glasgow, UK
* To whom correspondence should be addressed at: Division of Genetics and Molecular Medicine, King's College School of Medicine, 9th Floor Tower Wing, Guy's Hospital, Great Maze Pond, SE1 9RT London, UK. Tel: +44 2071887994; Fax: +44 2071888050; Email: richard.trembath{at}genetics.kcl.ac.uk
Received December 21, 2007; Revised February 21, 2008; Accepted March 18, 2008
Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage studies have clearly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), but have generated conflicting results for other genomic regions. To overcome this difficulty, we have carried out a genome-wide association scan, where we analyzed more than 408 000 SNPs in an initial sample of 318 cases and 288 controls. Outside of the MHC, we observed a single cluster of disease-associated markers, spanning 47 kb on chromosome 20q13. The analysis of two replication data sets confirmed this association, with SNP rs495337 yielding a combined P-value of 1.4 x 10–8 in an overall sample of 2679 cases and 2215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with five SNPs lying in the adjacent ZNF313 gene (also known as RNF114). Real-time PCR experiments showed that, unlike SPATA2, ZNF313 is abundantly expressed in skin, T-lymphocytes and dendritic cells. Furthermore, an analysis of the expression data available from the Genevar database indicated that rs495337 is associated with increased ZNF313 transcripts levels (P = 0.003), suggesting that the disease susceptibility allele may be a ZNF313 regulatory variant tagged by rs495337. Homology searches indicated that ZNF313 is a paralogue of TRAC-1, an ubiquitin ligase regulating T-cell activation. We performed cell-free assays and confirmed that like TRAC-1, ZNF313 binds ubiquitin via an ubiquitin-interaction motif (UIM). These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.