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      Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci

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          Abstract

          Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genomewide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genomewide significance (p < 5 × 10 −8). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3), and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2–dependent target of IL-17 signaling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.

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          Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

          George Mells, James A.B. Floyd, Katherine I. Morley … (2011)
          In addition to the HLA-locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). Twenty-eight loci were followed up in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 novel risk loci (P<5×10−8) and replicated all previously associated loci. Three further novel loci were identified by meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A, and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.
          Article 0 comments Cited 167 times – based on 0 reviews     Review now
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            The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease.

            Mark Aronica, Yi-Hui Lu, Xiaoxia Li … (2007)
            T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-kappaB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate-induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.
            Article 0 comments Cited 150 times – based on 0 reviews     Review now
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              Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.

              Ping Zhang, Yun Fang, Feng Wang … (2009)
              We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).
              Article 0 comments Cited 117 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101528555
                Journal ID (pubmed-jr-id): 37539
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                ISSN (Electronic): 2041-1723
                Publication date Nihms-submitted: 27 March 2015
                Publication date (Electronic): 05 May 2015
                Publication date Collection: 2015
                Publication date PMC-release: 05 November 2015
                Volume: 6
                Page: 7001
                Affiliations
                [1 ]Department of Biostatistics, Center for Statistical Genetics, University of Michigan Ann Arbor, MI 48109, USA
                [2 ]Division of Genetics and Molecular Medicine, King’s College London, London, UK
                [3 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [4 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
                [5 ]Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
                [6 ]Neuroscience Research, Centre for Addiction and Mental Health, Toronto, ON, Canada M5T 1R8
                [7 ]National Institute for Health Research (NIHR), Biomedical Research Centre, Guy’s and St. Thomas’ NHS Foundation Trust
                [8 ]Department of Dermatology, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, 24105 Kiel, Germany
                [9 ]Department of Pathophysiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, 50409 Tartu, Estonia
                [10 ]Department of Dermatology and Venerology, University of Tartu, 50409 Tartu, Estonia
                [11 ]Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia
                [12 ]Department of Dermatology, Linköping University, SE-581 83 Linköping, Sweden
                [13 ]Dept of Dermatology, University of Utah, Salt Lake City, UT 84132
                [14 ]Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada
                [15 ]Department of Medicine, Division of Dermatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario M5T 2S8
                [16 ]Department of Medicine, Memorial University, St. John’s, Newfoundland A1C 5B8, Canada
                [17 ]Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
                [18 ]Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
                [19 ]Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI, 48105, USA
                Author notes
                [‡ ]Corresponding authors: James T. Elder, 7412 Medical Sciences Building 1, University of Michigan Medical School, 1301 E. Catherine, Ann Arbor, Michigan 48109-5675, USA, phone (734) 647-8070, jelder@ 123456umich.edu . Richard C. Trembath, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 2AD, UK, vp-health@ 123456qmul.ac.uk . Goncalo R. Abecasis, Department of Biostatistics, Center for Statistical Genetics, School of Public Health M4614 SPH I, University of Michigan, Box 2029, Ann Arbor, MI 48109-2029, USA, phone (734) 763-4901, goncalo@ 123456umich.edu
                Article
                Manuscript ID: NIHMS675370
                DOI: 10.1038/ncomms8001
                PMC ID: 4422106
                PubMed ID: 25939698
                SO-VID: 86f410ae-3856-40f9-b350-64a746cc2d9a
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