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Genome-wide association analysis identifies three psoriasis susceptibility loci

Abstract

We carried out a meta-analysis of two recent psoriasis genome-wide association studies1,2 with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10−11), one at FBXL19 (rs10782001, combined P = 9 × 10−10) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10−8). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10−5; rs10782001, combined P = 4 × 10−8; and rs12586317, combined P = 6 × 10−5) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10−8; rs10782001, combined P = 2 × 10−6; and rs12586317, combined P = 1 × 10−6). We also replicated a recently identified3 association signal near RNF114 (rs495337, combined P = 2 × 10−7).

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Figure 1: Evidence for psoriasis association in four genomic regions including the three new loci attaining genome-wide significance and the confirmed RNF114 region.
Figure 2: Expression data for notable candidate genes within the three psoriasis-associated regions.

References

  1. Nair, R.P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat. Genet. 41, 199–204 (2009).

    Google Scholar 

  2. Ellinghaus, E. et al. Genome-wide association study reveals association of psoriasis with TRAF3IP2. Nat. Genet. (in the press) (2010).

  3. Capon, F. et al. Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum. Mol. Genet. 17, 1938–1945 (2008).

    Google Scholar 

  4. Nestle, F.O., Di Meglio, P., Qin, J.Z. & Nickoloff, B.J. Skin immune sentinels in health and disease. Nat. Rev. Immunol. 9, 679–691 (2009).

    Google Scholar 

  5. Gladman, D.D. Psoriatic arthritis. in Moderate to Severe Psoriasis (eds. Koo, J., Lee, C.S., Lebwohl, M., Weinstein, G.D. & Gottlieb, A.B.) 239–258 (Informa Health Care, New York, 2009).

  6. Gelfand, J.M. et al. Risk of myocardial infarction in patients with psoriasis. J. Am. Med. Assoc. 296, 1735–1741 (2006).

    Google Scholar 

  7. Makredes, M., Robinson, D. Jr., Bala, M. & Kimball, A.B. The burden of autoimmune disease: a comparison of prevalence ratios in patients with psoriatic arthritis and psoriasis. J. Am. Acad. Dermatol. 61, 405–410 (2009).

    Google Scholar 

  8. Russell, T.J., Schultes, L.M. & Kuban, D.J. Histocompatibility (HL-A) antigens associated with psoriasis. N. Engl. J. Med. 287, 738–740 (1972).

    Google Scholar 

  9. Tiilikainen, A., Lassus, A., Karvonen, J., Vartiainen, P. & Julin, M. Psoriasis and HLA-Cw6. Br. J. Dermatol. 102, 179–184 (1980).

    Google Scholar 

  10. Nair, R.P. et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 78, 827–851 (2006).

    Google Scholar 

  11. Hollox, E.J. et al. Psoriasis is associated with increased beta-defensin genomic copy number. Nat. Genet. 40, 23–25 (2008).

    Google Scholar 

  12. Elder, J.T. et al. Molecular dissection of psoriasis: integrating genetics and biology. J. Invest. Dermatol. 130, 1213–1236 (2009).

    Google Scholar 

  13. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Google Scholar 

  14. Chandran, V., Schentag, C.T. & Gladman, D.D. Sensitivity and specificity of the CASPAR criteria for psoriatic arthritis in a family medicine clinic setting. J. Rheumatol. 35, 2069–2070, author reply 2070 (2008).

    Google Scholar 

  15. Zaba, L.C., Krueger, J.G. & Lowes, M.A. Resident and “inflammatory” dendritic cells in human skin. J. Invest. Dermatol. 129, 302–308 (2009).

    Google Scholar 

  16. Melchiorri, C. et al. Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum. 41, 2165–2174 (1998).

    Google Scholar 

  17. Cal, S. et al. Identification and characterization of human polyserase-3, a novel protein with tandem serine-protease domains in the same polypeptide chain. BMC Biochem. 7, 9 (2006).

    Google Scholar 

  18. Lu, T. et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc. Natl. Acad. Sci. USA 107, 46–51 (2010).

    Google Scholar 

  19. Jin, J. et al. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 18, 2573–2580 (2004).

    Google Scholar 

  20. Chung, J.S., Bonkobara, M., Tomihari, M., Cruz, P.D. Jr. & Ariizumi, K. The DC-HIL/syndecan-4 pathway inhibits human allogeneic T-cell responses. Eur. J. Immunol. 39, 965–974 (2009).

    Google Scholar 

  21. Todd, J.A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857–864 (2007).

    Google Scholar 

  22. Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

    Google Scholar 

  23. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Google Scholar 

  24. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    Google Scholar 

  25. Huang, L. et al. Genotype-imputation accuracy across worldwide human populations. Am. J. Hum. Genet. 84, 235–250 (2009).

    Google Scholar 

  26. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).

    Google Scholar 

  27. Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).

    Google Scholar 

  28. Horton, R. et al. Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889–899 (2004).

    Google Scholar 

  29. de Cid, R. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat. Genet. 41, 211–215 (2009).

    Google Scholar 

  30. Abu Bakar, S., Hollox, E.J. & Armour, J.A. Allelic recombination between distinct genomic locations generates copy number diversity in human beta-defensins. Proc. Natl. Acad. Sci. USA 106, 853–858 (2009).

    Google Scholar 

  31. Gudjonsson, J.E. et al. Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin. J. Invest. Dermatol. 129, 2795–2804 (2009).

    Google Scholar 

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Acknowledgements

The authors wish to thank the many psoriasis and PsA cases and normal controls who participated in this study and to acknowledge the key contributions of K. Callis Duffin, D. Goldgar and B. Jian Feng of the University of Utah and C. Helms of Washington University at St. Louis to the CASP study. This research was supported by grants R01AR42742, R01AR050511, R01AR054966, R01AR050266, R01HG002651 and U01HG005214 from the US National Institutes of Health, by the Ann Arbor Veterans Affairs Hospital, by the German Ministry of Education and Research through the National Genome Research Network (BMFT 01GS 0171/ BMBF NUW-S23T10) and by the Krembil Foundation and the Canadian Institutes of Health Research.

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Authors

Contributions

R.P.N., P.E.S. and J.T.E. performed SNP selection, data analysis and prepared the figures and tables. R.P.N., T.T., P.E.S., P.R. and E.E. performed genotyping. P.E.S., Y.L. and J.D. performed genotype imputation and association analyses, and P.E.S., J.E.G., and J.D. performed the expression analyses. G.R.A. helped with statistical analyses and interpretation of results. R.P.N., T.T., J.J.V., R.I., M.W., S.W., B.E., C.G., H.E.W., H.W.L., P.R., M.K., U.M. and D.D.G. coordinated subject recruitment and collected phenotype data. J.T.E., G.G.K. and A.M.B. contributed genotypes and phenotypes from the CASP discovery GWAS. J.T.E. and P.E.S. drafted the manuscript; R.P.N., G.R.A., E.E., M.W. and A.F. edited the manuscript; and J.T.E. planned and supervised the study. All authors approved the final draft.

Corresponding author

Correspondence to James T Elder.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Tables 1–6 and Supplementary Figures 1 and 2. (PDF 2747 kb)

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Stuart, P., Nair, R., Ellinghaus, E. et al. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet 42, 1000–1004 (2010). https://doi.org/10.1038/ng.693

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