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Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3


Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of thyrotoxicosis. We conducted a genome-wide association study (GWAS) and a replication study with a total of 123 southern Chinese with TPP (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (rs312691: odds ratio (OR) = 3.3; Pmeta-analysis = 1.8 × 10−14). All subjects with TPP also had Graves' disease, and subsequent TPP versus Graves' disease comparison confirmed that the association at 17q24.3 was specific to TPP. The area under the curve (AUC) of rs312691 genotype for risk prediction of TPP in subjects with Graves' disease was 0.73. Expression quantitative trait locus (eQTL) analysis identified SNPs in the region flanking rs312691 (±10 kb) that could potentially affect KCNJ2 expression (P = 0.0001). Our study has identified a susceptibility locus associated with TPP and provides insight into the causes of TPP.

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Figure 1: Regional association plot of the 17q24.3 locus.
Figure 2: Regional genome-wide association and KCNJ2 eQTL plot of the 17q24.3 locus.


  1. Kung, A.W. Clinical review: thyrotoxic periodic paralysis: a diagnostic challenge. J. Clin. Endocrinol. Metab. 91, 2490–2495 (2006).

    Article  CAS  Google Scholar 

  2. Ryan, D.P. et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell 140, 88–98 (2010).

    Article  CAS  Google Scholar 

  3. Swets, J.A. Measuring the accuracy of diagnostic systems. Science 240, 1285–1293 (1988).

    Article  CAS  Google Scholar 

  4. Hanley, J.A. & McNeil, B.J. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143, 29–36 (1982).

    Article  CAS  Google Scholar 

  5. Nica, A.C. et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 7, e1002003 (2011).

    Article  CAS  Google Scholar 

  6. Jongjaroenprasert, W. et al. A genome-wide association study identifies novel susceptibility genetic variation for thyrotoxic hypokalemic periodic paralysis. J. Hum. Genet. 57, 301–304 (2012).

    Article  CAS  Google Scholar 

  7. Liu, Y. et al. The human inward rectifier K+ channel subunit kir5.1 (KCNJ16) maps to chromosome 17q25 and is expressed in kidney and pancreas. Cytogenet. Cell Genet. 90, 60–63 (2000).

    Article  CAS  Google Scholar 

  8. D'Adamo, M.C. et al. Genetic inactivation of Kcnj16 identifies Kir5.1 as an important determinant of neuronal PCO2/pH sensitivity. J. Biol. Chem. 286, 192–198 (2011).

    Article  CAS  Google Scholar 

  9. Hibino, H. et al. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev. 90, 291–366 (2010).

    Article  CAS  Google Scholar 

  10. Cheng, W.W., D'Avanzo, N., Doyle, D.A. & Nichols, C.G. Dual-mode phospholipid regulation of human inward rectifying potassium channels. Biophys. J. 100, 620–628 (2011).

    Article  CAS  Google Scholar 

  11. Dassau, L., Conti, L.R., Radeke, C.M., Ptacek, L.J. & Vandenberg, C.A. Kir2.6 regulates the surface expression of Kir2.x inward rectifier potassium channels. J. Biol. Chem. 286, 9526–9541 (2011).

    Article  CAS  Google Scholar 

  12. Tawil, R. et al. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann. Neurol. 35, 326–330 (1994).

    Article  CAS  Google Scholar 

  13. Andersen, E.D., Krasilnikoff, P.A. & Overvad, H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr. Scand. 60, 559–564 (1971).

    Article  CAS  Google Scholar 

  14. Andelfinger, G. et al. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am. J. Hum. Genet. 71, 663–668 (2002).

    Article  CAS  Google Scholar 

  15. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  16. Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

    Article  Google Scholar 

  17. Chen, J. et al. Genetic structure of the Han Chinese population revealed by genome-wide SNP variation. Am. J. Hum. Genet. 85, 775–785 (2009).

    Article  CAS  Google Scholar 

  18. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  19. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    Article  CAS  Google Scholar 

  20. Yang, T.P. et al. Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies. Bioinformatics 26, 2474–2476 (2010).

    Article  CAS  Google Scholar 

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We are grateful to all study participants and investigators at the individual centers for taking part. We are extremely grateful to all investigators who contributed to the generation of this data set. P.-C.S. was supported by The University of Hong Kong Strategic Research Theme of Genomics.

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Authors and Affiliations



A.W.C.K. obtained financial support. A.W.C.K. and C.-L.C. designed the study. A.W.C.K., P.-C.S. and C.-L.C. designed and supervised data analyses. C.-L.C. performed data analyses. K.-S.L. managed and prepared DNA samples. A.Y.Y.H., K.-K.L., S.-C.T., E.Y.F.L., J.L., M.-W.T., K.-W.C., C.-Y.Y., Y.-C.W., E.Y.N.C., V.H.F.H., H.-K.P., C.-S.H. and A.W.C.K. ascertained and recruited samples. A.W.C.K. and C.-L.C. drafted the manuscript. A.W.C.K., P.-C.S. and C.-L.C. revised the manuscript. All authors critically reviewed and approved the manuscript.

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Correspondence to Ching-Lung Cheung, Pak-Chung Sham or Annie W C Kung.

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The authors declare no competing financial interests.

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Cheung, CL., Lau, KS., Ho, A. et al. Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3. Nat Genet 44, 1026–1029 (2012).

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