Letter | Published:

A genome-wide association study identifies two new risk loci for Graves' disease

Nature Genetics volume 43, pages 897901 (2011) | Download Citation

Abstract

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (Pcombined = 6.85 × 10−10 for rs9355610) and an intergenic region at 4p14 (Pcombined = 1.08 × 10−13 for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.

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Acknowledgements

We thank all subjects for participating in this study. This work was supported in part by the National Natural Science Foundation of China (30971595, 30971383 and 31000556), Chinese National Natural Science Fund for Distinguished Young Scholars (30625019), Chinese High-Tech Program (2007AA02Z175 and 2009AA022709), Shanghai Science and Technology Committee (10JC1410400, 09DZ2291900, 09JC1411300 and 10ZR1421400) and Program for Innovative Research Team of Shanghai Municipal Education Committee.

Author information

Author notes

    • Xun Chu
    • , Chun-Ming Pan
    • , Shuang-Xia Zhao
    • , Jun Liang
    • , Guan-Qi Gao
    •  & Xiao-Mei Zhang

    These authors contributed equally to this work.

    • Guang Ning
    • , Zhu Chen
    • , Jia-Lun Chen
    • , Sai-Juan Chen
    • , Wei Huang
    •  & Huai-Dong Song

    These authors jointly directed this work.

Affiliations

  1. State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China.

    • Xun Chu
    • , Chun-Ming Pan
    • , Shuang-Xia Zhao
    • , Li-Qiong Xue
    • , Wei Liu
    • , Fang Xie
    • , Shao-Ying Yang
    • , Jing-Yi Shi
    • , Chun-Lin Zuo
    • , Jin-Xiu Shi
    • , Bing-Li Liu
    • , Cui-Cui Guo
    • , Ming Zhan
    • , Zhao-Hui Gu
    • , Xiao-Na Zhang
    • , Fei Sun
    • , Zhi-Quan Wang
    • , Zhi-Yi Song
    • , Ting Guo
    • , Huang-Ming Cao
    • , Jun-Hua Ma
    • , Bing Han
    • , Ping Li
    • , He Jiang
    • , Qiu-Hua Huang
    • , Zhu Chen
    • , Sai-Juan Chen
    • , Wei Huang
    •  & Huai-Dong Song
  2. Department of Genetics, Shanghai-Ministry of Science and Technology (MOST) Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center, Shanghai, China.

    • Xun Chu
    • , Min Shen
    • , Fang Xie
    • , Hai-Feng Wang
    • , Wei-Wei Sun
    • , Jin-Xiu Shi
    •  & Wei Huang
  3. Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai, China.

    • Chun-Ming Pan
    • , Shuang-Xia Zhao
    • , Ting Guo
    • , Ping Li
    • , Guang Ning
    • , Jia-Lun Chen
    •  & Huai-Dong Song
  4. Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, Jiangsu Province, China.

    • Jun Liang
    •  & Cai-Yan Zou
  5. Department of Endocrinology, The People's Hospital of Linyi, Linyi, Shandong Province, China.

    • Guan-Qi Gao
    •  & Wen-Hua Du
  6. Department of Endocrinology, The First Hospital Affiliated to Bengbu Medical College, Bengbu, Anhui Province, China.

    • Xiao-Mei Zhang
    •  & Wei-Hua Sun
  7. Department of Endocrinology, The Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu Province, China.

    • Guo-Yue Yuan
  8. Department of Endocrinology and Gout Laboratory, Medical School Hospital of Qingdao University, Qingdao, Shandong Province China.

    • Chang-Gui Li
  9. Department of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Liming Liang
  10. Department of Endocrinology, Xiehe Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian Province, China.

    • Li-Bin Liu
  11. Department of Endocrinology, Fujian Province Hospital, Fuzhou, Fujian Province, China.

    • Gang Chen
  12. Department of Endocrinology, Xin-Hua Hospital Affiliated to SJTU School of Medicine, Shanghai, China.

    • Qing Su
  13. Department of Endocrinology, The First People's Hospital Affiliated to SJTU, Shanghai, China.

    • Yong-De Peng
  14. Department of Endocrinology, Shandong Province Hospital, Shandong University, Jinan, Shandong Province, China.

    • Jia-Jun Zhao

Consortia

  1. The China Consortium for the Genetics of Autoimmune Thyroid Disease

Authors

    Contributions

    Z.C. was responsible for the coordination of the project. The writing team consisted of H.-D.S., X.C., W.H., S.-X.Z., J.-L.C., S.-J.C. and Z.C. Z.C., H.-D.S., W.H., G.N., J.-L.C. and S.-J.C. contributed to the study design. H.-D.S., W.H., C.-M.P. and X.C. contributed to the project management. H.-D.S., J.L., G.-Q.G., X.-M.Z., C.-M.P., G.-Y.Y., C.-G.L., L.-Q.X., W.L., S.-Y.Y., S.-X.Z., W.-H.D., C.-L.Z., B.-L.L., X.-N.Z., F.S., Z.-Q.W., Z.-Y.S., C.-Y.Z., W.-H.S., H.-M.C., J.-H.M., B.H., P.L., H.J., C.-C.G., M.Z., L.-B.L., G.C., Q.S., Y.-D.P. and J.-J.Z. took part in the collection of clinical samples and DNA and sample quality control. W.H., H.-F.W., M.S., X.C., F.X., W.-W.S. and J.-X.S. contributed to whole-genome scan genotyping. C.-M.P., J.-Y.S., L.-Q.X., W.L., S.-Y.Y., S.-X.Z., T.G., X.C., M.S., F.X. and W.-W.S. took part in replication genotyping. S.-X.Z., C.-M.P., M.Z., B.-L.L., C.-C.G., Z.-H.G., W.L., S.-Y.Y., L.-Q.X. and Q.-H.H. contributed to cloning of GDCG4p14 and real-time RT-PCR. X.C., W.H., J.-X.S., H.-D.S., S.-X.Z., Z.-H.G., J.-L.C., S.-J.C. and Z.C. took part in the statistical analysis. S.-X.Z. and L.L. performed imputation and cis-eQTL analysis.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Guang Ning or Zhu Chen or Jia-Lun Chen or Sai-Juan Chen or Wei Huang or Huai-Dong Song.

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      Supplementary Note, Supplementary Figures 1–9 and Supplementary Tables 1–11.

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    DOI

    https://doi.org/10.1038/ng.898

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