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A large-scale screen for coding variants predisposing to psoriasis

Abstract

To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis.

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Figure 1: Haplotype analyses in FUT2, IL23R, GJB2 and TARBP1.

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Acknowledgements

We thank the individuals who participated in this project and their families. We also want to thank L. Wu, D. Li, Y. Shi, J. Shen, L. Song, Y. Xue, J. Jv, Y. Sheng and J. Gao who participated in the analysis of exome sequencing data. We thank the State Key Laboratory Incubation Base of Dermatology, Ministry of National Science and Technology (Hefei, China). This study was funded by the Key Program of the National Natural Science Foundation of China (81130031), the National Science Fund for Excellent Young Scholars (81222022), the Outstanding Talents of Organization Department of the CPC (Communist Party of China) Central Committee program, the Local Universities Characteristics and Advantages of Discipline Development Program of the Ministry of Finance of China and the General Program of the National Natural Science Foundation of China (81072461, 30971644, 31171224, 31000528, 81000692, 81071285, 81172866, 81172591 and 31200939), New Century Excellent Talents in University (NCET-11-0889), and the Science and Technological Fund of Anhui Province for Outstanding Youth (1108085J10) as well as the Pre-National Basic Research Program of China (973 Plan; 2012CB722404), the National Basic Research Program of China (973 Plan; 2009CB825404), the State Key Development Program for Basic Research of China (973 Program; 2011CB809203), the Chinese High-Tech (863) Program (2012AA02A201), the Enterprise Key Laboratory, supported by Guangdong Province, and the Shenzhen Key Laboratory of Transomics Biotechnologies (CXB201108250096A), and the National High-Tech Research & Development Program (2012AA020206).

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Xuejun Zhang conceived this study and obtained financial support. Xuejun Zhang, J.W., Yingrui Li and L.S. participated in study design and were responsible for project management. H.C., Y.Q., Q.C., C.Q., Y.C., F.T., H.L., F. Xiao, J.H., D.S., A.Z., C.Z., X.F., H. Tian, Z.W., F.W., B.Y., B.L., G.W., Y.S., L.D., J.S., T.L., Xiuyun Zhang, Yuzhen Li, C.H., A.X., L.W., Xiaohang Zhao, X.G., J.X., F. Zhang and J.Z. conducted sample selection and data management, undertook recruitment, collected phenotype data, undertook related data handling and calculations, managed recruitment and obtained biological samples. H. Tang, X.J., Yang Li, H.J., X.T., X.Y., J.M., R.W., X. Zuo, Y.Z., X. Yin, H.S., Xia Zhao, F. Xu, Q.L., L.L., H.F., S.H., X.X., Y.R., Q.G., X.W., M.X., L.Y. and R.C. designed the bioinformatics and experimental sections, coordinated the collection, maintained project procedures and performed data analysis. F. Zhou, G.C. and X. Zheng performed genotyping analysis. H. Tang, X.J., X. Zuo, X.T. and H.C. undertook data processing, statistical analysis and bioinformatics investigations. H. Tang, X.J., L.S., X.T., Yang Li and J.L. cowrote the manuscript. All authors contributed to the final version of the manuscript, with Xuejun Zhang, J.W., S.Y., L.S., Yingrui Li, H. Tang, X.J., X.T., H.J. and Yang Li having key roles.

Corresponding authors

Correspondence to Jun Wang or Xuejun Zhang.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–6, 10–17 and 19 (PDF 4351 kb)

Supplementary Table 7

742 genes by gene-based analysis from exome sequencing and targeted sequencing data (XLSX 395 kb)

Supplementary Table 8

Targeted sequencing of 565 immune related genes (not included psoriasis GWAS loci) and results of gene-based test (XLSX 222 kb)

Supplementary Table 9

Targeted sequencing of 57 genes in psoriasis GWAS loci and results of gene-based test (XLSX 37 kb)

Supplementary Table 18

Depth and coverage per gene (XLSX 273 kb)

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Tang, H., Jin, X., Li, Y. et al. A large-scale screen for coding variants predisposing to psoriasis. Nat Genet 46, 45–50 (2014). https://doi.org/10.1038/ng.2827

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