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

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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Figure 1: Genome-wide association results for SNPs in the MHC region at 6p21–22.
Figure 2: Regional plots of association results and expression analysis of candidate genes.

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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.

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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.

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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The author declare no competing financial interests.

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Supplementary Note, Supplementary Figures 1–9 and Supplementary Tables 1–11. (PDF 1820 kb)

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The China Consortium for the Genetics of Autoimmune Thyroid Disease. A genome-wide association study identifies two new risk loci for Graves' disease. Nat Genet 43, 897–901 (2011). https://doi.org/10.1038/ng.898

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