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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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).

Author information

Author notes

    • Huayang Tang
    • , Xin Jin
    • , Yang Li
    • , Hui Jiang
    •  & Xianfa Tang

    These authors contributed equally to this work.

Affiliations

  1. Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, China.

    • Huayang Tang
    • , Yang Li
    • , Xianfa Tang
    • , Hui Cheng
    • , Gang Chen
    • , Fusheng Zhou
    • , Xianbo Zuo
    • , Xiaodong Zheng
    • , Xianyong Yin
    • , Cheng Quan
    • , Yong Cui
    • , Fengli Xiao
    • , Anping Zhang
    • , Xing Fan
    • , Zaixing Wang
    • , Bo Liang
    • , Yunqing Ren
    • , Liangdan Sun
    • , Jianjun Liu
    • , Sen Yang
    •  & Xuejun Zhang
  2. BGI-Shenzhen, Shenzhen, China.

    • Xin Jin
    • , Hui Jiang
    • , Xu Yang
    • , Junpu Mei
    • , Renhua Wu
    • , Yong Zhang
    • , Haojing Shao
    • , Xia Zhao
    • , Fengping Xu
    • , Qibin Li
    • , Liya Lin
    • , Huiling Fu
    • , Shaowei Huang
    • , Xuefeng Xie
    • , Qingquan Gu
    • , Xueli Wu
    • , Min Xia
    • , Lin Yang
    • , Yingrui Li
    •  & Jun Wang
  3. School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China.

    • Xin Jin
  4. Department of Dermatology, Jining No. 1 People's Hospital, Jining, Shandong, China.

    • Ying Qiu
    • , Fangzhen Tian
    • , Dongmei Shi
    • , Tianhang Li
    •  & Xiuyun Zhang
  5. Department of Dermatology, Second Hospital, Chengdu, China.

    • Qi Cai
  6. Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Science, Jinan, China.

    • Hong Liu
    • , Hongqing Tian
    • , Baoqi Yang
    •  & Furen Zhang
  7. Department of Dermatology, Affiliated Hospital of Inner Mongolia Medical College, Huhehot, China.

    • Jianwen Han
  8. Department of Dermatology, Peking University People's Hospital, Beijing, China.

    • Cheng Zhou
    • , Fang Wang
    • , Guangdong Wen
    •  & Jianzhong Zhang
  9. State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and Center of Basic Medical Sciences, Navy General Hospital, Beijing, China.

    • Yulin Sun
    •  & Xiaohang Zhao
  10. Department of Dermatology, Second Affiliated Hospital of Harbin Medical University, Harbin, China.

    • Lin Dang
    •  & Yuzhen Li
  11. Department of Dermatology, Third People's Hospital of Hangzhou, Hangzhou, China.

    • Junjun Shan
    •  & Aie Xu
  12. Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, China.

    • Chundi He
    •  & Xinghua Gao
  13. School of Life Sciences, Peking University, Beijing, China.

    • Liping Wei
  14. Department of Dermatology, Huashan Hospital of Fudan University, Shanghai, China.

    • Jinhua Xu
    •  & Xuejun Zhang
  15. Institute of Biophysics of the Chinese Academy of Sciences, Beijing, China.

    • Runsheng Chen
  16. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Jun Wang
  17. Department of Biology, University of Copenhagen, Copenhagen, Denmark.

    • Jun Wang

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jun Wang or Xuejun Zhang.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Tables 1–6, 10–17 and 19

Excel files

  1. 1.

    Supplementary Table 7

    742 genes by gene-based analysis from exome sequencing and targeted sequencing data

  2. 2.

    Supplementary Table 8

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

  3. 3.

    Supplementary Table 9

    Targeted sequencing of 57 genes in psoriasis GWAS loci and results of gene-based test

  4. 4.

    Supplementary Table 18

    Depth and coverage per gene

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DOI

https://doi.org/10.1038/ng.2827