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Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2

Abstract

Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 × 10−10 for rs13210247 and combined P = 1.24 × 10−16 for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 × 10−12 for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family.

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Figure 1: Regional plot of TRAF3IP2.

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Acknowledgements

We thank all individuals with psoriasis who participated in this study, their families and their physicians for their cooperation. We acknowledge the cooperation of Genizon Biosciences. We wish to thank T. Wesse, T. Henke, C. Fürstenau, S. Ehlers, M. Davids and R. Vogler for expert technical help. We thank J.R. Hov for helpful discussions. This study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN), the PopGen biobank and the KORA (Cooperative Research in the Region of Augsburg) research platform. KORA was initiated and financed by the Helmholtz Zentrum München-National Research Center for Environmental Health, which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The project received infrastructure support through the Deutsche Forschungsgemeinschaft (DFG) clusters of excellence 'Multimodal Computing and Interaction' and 'Inflammation at Interfaces'. This research was also supported by grants R01-AR42742, R01-AR050511 and R01-AR054966 from the US National Institutes of Health.

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E.E. performed SNP selection, genotyping, data analysis and prepared the figures and tables. A.F. helped with data analysis. D.E. performed imputation, data analysis and generated the regional plots. P.E.S., J.G., J.D. and Y.L. performed the expression and expression quantitative trait loci analyses. S.W.S. and S.L. performed small hairpin RNA (shRNA) experiments. G.R.A. helped with statistical analyses and interpretation of the results. M.A. and G.M. performed in silico protein analyses. M.W., U.M., S.W., B.E. and M.K. coordinated the recruitment and collected phenotype data of panels A and B. C.G. and H.E.W. provided the KORA control samples. J.T.E., J.J.V., R.P.N., T.T., S.D., J.V.R., M.B., H.F., C.R., P.R. and D.D.G. provided the replication samples C through F and the respective genotypes and phenotypes. T.H.K., R.P.N. and D.K. helped with genotyping. E.E. and A.F. drafted the manuscript. D.E., M.W., J.T.E., T.H.K. and S.S. edited the manuscript. A.F. planned and supervised the study. All authors approved the final draft.

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Correspondence to Michael Weichenthal or Andre Franke.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 and Supplementary Tables 1–3. (PDF 2989 kb)

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Ellinghaus, E., Ellinghaus, D., Stuart, P. et al. Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet 42, 991–995 (2010). https://doi.org/10.1038/ng.689

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