Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3
Abstract
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; P(meta-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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PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Self-citationThe meaning and use of the area under a receiver operating characteristic (ROC) curve.
Hanley, J. A., & McNeil, B. J. (1982) · Radiology · doi:10.1148/radiology.143.1.7063747 · Cited by 21,856 · see citing works
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
Measuring the Accuracy of Diagnostic Systems
Swets, J. A. (1988) · Science · doi:10.1126/science.3287615 · Cited by 10,058 · see citing works
LocusZoom: regional visualization of genome-wide association scan results
Pruim, R. J., Welch, R. P., Sanna, S., Teslovich, T. M., Chines, P. S., Gliedt, T. P., Boehnke, M., Abecasis, G. R., & Willer, C. J. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq419 · Cited by 2,707 · see citing works
MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes
Li, Y., Willer, C. J., Ding, J., Scheet, P., & Abecasis, G. R. (2010) · Genetic Epidemiology · doi:10.1002/gepi.20533 · Cited by 1,843 · see citing works
Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles
Hibino, H., Inanobe, A., Furutani, K., Murakami, S., Findlay, I., & Kurachi, Y. (2010) · Physiological Reviews · doi:10.1152/physrev.00021.2009 · Cited by 1,518 · see citing works
The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study
Nica, A. C., Parts, L., Glass, D., Nisbet, J. P., Barrett, A., Sekowska, M., Travers, M. E., Potter, S., Grundberg, E., Small, K. S., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002003 · Cited by 395 · see citing works
Thyrotoxic Periodic Paralysis: A Diagnostic Challenge
Kung, A. W. C. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0356 · Cited by 371 · see citing works
Self-citationTawil, R., Ptáček, L. J., Pavlakis, S. G., Vivo, D. C. D., Penn, A. S., Özdemır, C., & Griggs, R. C. (1994) · Annals of Neurology · doi:10.1002/ana.410350313 · Cited by 362 · see citing works
Genetic Structure of the Han Chinese Population Revealed by Genome-wide SNP Variation
Chen, J., Zheng, H., Bei, J.-X., Sun, L., Jia, W.-H., Li, T., Zhang, F., Seielstad, M., Zeng, Y.-X., Zhang, X., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.10.016 · Cited by 315 · see citing works
Ryan, D. P., Dias da Silva, M. R., Soong, T. W., Fontaine, B., Donaldson, M. R., Kung, A. W. C., Jongjaroenprasert, W., Liang, M. C., Khoo, D. H. C., Cheah, J. S., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.024 · Cited by 311 · see citing works
Self-citationINTERMITTENT MUSCULAR WEAKNESS, EXTRASYSTOLES, AND MULTIPLE DEVELOPMENTAL ANOMALIES
Andersen, E. D., Krasilnikoff, P. A., & Overvad, H. (1971) · Acta Paediatrica · doi:10.1111/j.1651-2227.1971.tb06990.x · Cited by 304 · see citing works
Yang, T.-P., Beazley, C., Montgomery, S. B., Dimas, A. S., Gutiérrez‐Arcelus, M., Stranger, B. E., Deloukas, P., & Dermitzakis, E. T. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq452 · Cited by 292 · see citing works
KCNJ2 Mutation Results in Andersen Syndrome with Sex-Specific Cardiac and Skeletal Muscle Phenotypes
Andelfinger, G., Tapper, A. R., Welch, R. C., Vanoye, C. G., George, A. L., & Benson, D. W. (2002) · The American Journal of Human Genetics · doi:10.1086/342360 · Cited by 262 · see citing works
Dual-Mode Phospholipid Regulation of Human Inward Rectifying Potassium Channels
Cheng, W. W. L., D’Avanzo, N., Doyle, D., & Nichols, C. G. (2011) · Biophysical Journal · doi:10.1016/j.bpj.2010.12.3724 · Cited by 75 · see citing works
D’Adamo, M. C., Shang, L., Imbrici, P., Brown, S. D. M., Pessia, M., & Tucker, S. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.189290 · Cited by 53 · see citing works
Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels
Dassau, L., Conti, L. R., Radeke, C. M., Ptáček, L. J., & Vandenberg, C. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.170597 · Cited by 43 · see citing works
Jongjaroenprasert, W., Phusantisampan, T., Mahasirimongkol, S., Mushiroda, T., Hirankarn, N., Snabboon, T., Chanprasertyotin, S., Tantiwong, P., Soonthornpun, S., Rattanapichart, P., et al. (2012) · Journal of Human Genetics · doi:10.1038/jhg.2012.20 · Cited by 33 · see citing works
Liu, Y., McKenna, E. J., Figueroa, D. J., Blevins, R. A., Austin, C. P., Bennett, P. B., & Swanson, R. (2000) · Cytogenetic and Genome Research · doi:10.1159/000015662 · Cited by 24 · see citing works
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Ambrosini, E., Sicca, F., Brignone, M. S., D’Adamo, M. C., Napolitano, C., Servettini, I., Moro, F., Ruan, Y., Guglielmi, L., Pieroni, S., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu201 · Cited by 86 · see citing works
Insight in Genome-Wide Association of Metabolite Quantitative Traits by Exome Sequence Analyses
Demirkan, A., Henneman, P., Verhoeven, A., Dharuri, H. K., Amin, N., van Klinken, J. B., Karssen, L. C., de Vries, B., Meissner, A., Göraler, S., et al. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1004835 · Cited by 75 · see citing works
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Wood-Allum, C. A., & Shaw, P. J. (2013) · Handbook of clinical neurology · doi:10.1016/b978-0-7020-4087-0.00048-6 · Cited by 45 · see citing works
Wang, J., Zhang, C., Zhang, Z., Zheng, Z., Sun, D., Yang, Q., Hadadi, C. A., Li, D., Xu, X., Xiong, M., et al. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.02.004 · Cited by 34 · see citing works
Zhao, S., Liu, W., Liang, J., Gao, G.-Q., Zhang, X., Yao, Y., Wang, H., Yuan, F., Xue, L., Ma, Y., et al. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.3348 · Cited by 22 · see citing works
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Song, I.-W., Sung, C., Chen, C.-H., Cheng, C.-J., Yang, S.-S., Chou, Y., Yang, J.-H., Chen, Y.-T., Wu, J., & Lin, S. (2016) · Neurology · doi:10.1212/wnl.0000000000002524 · Cited by 19 · see citing works
Li, X., Yao, S., Xiang, Y., Zhang, X., Wu, X., Luo, L., Huang, H., Zhu, M., Wan, H., & Hong, D. (2015) · BMC Neurology · doi:10.1186/s12883-015-0290-8 · Cited by 18 · see citing works
Genetic variants of interleukin-4 gene in autoimmune thyroid diseases: An updated meta-analysis
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Paninka, R. M., Carlos-Lima, E., Lindsey, S. C., Kunii, I. S., Dias-da-Silva, M. R., & Arcísio-Miranda, M. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.01.019 · Cited by 12 · see citing works
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Rolim, A. L., Lindsey, S. C., Kunii, I. S., Crispim, F., Moisés, R. S., Maciel, R. M. B., & Dias-da-Silva, M. R. (2014) · Journal of Molecular Endocrinology · doi:10.1530/jme-14-0083 · Cited by 5 · see citing works
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Qin, Y., Liu, Y., Wang, Y., You, C., Li, L.-N., Zhou, X., Lv, W.-M., Hong, S.-H., & Xiao, L. (2022) · World Journal of Clinical Cases · doi:10.12998/wjcc.v10.i21.7483 · Cited by 4 · see citing works
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Díaz‐Manera, J., Querol, L., Alejaldre, A., Rojas‐García, R., Fransi, A. R., Gallardo, E., & Illa, I. (2014) · Journal of Human Genetics · doi:10.1038/jhg.2014.43 · Cited by 3 · see citing works
Wang, X., Chow, C. C., Yao, X., Ko, G. T. C., Cockram, C. S., Kwok, H.-K., Zhang, J., & Tang, N. L. S. (2013) · Clinical Endocrinology · doi:10.1111/cen.12277 · Cited by 3 · see citing works
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He, Z., Gong, Z., Jiao, S., Xiong, W., Hao, X., Cui, J., & Zhang, J. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1364027 · Cited by 2 · see citing works
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Yang, R.-R., Jurkat‐Rott, K., Cao, J., Wang, G., Seelig, H.-P., Yang, C.-P., Liu, G.-B., Pan, L., Zheng, H., & Lehmann‐Horn, F. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.3918 · Cited by 2 · see citing works
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Mangaraj, S., Jena, D., Mishra, P. K., Choudhury, A. K., Mohanty, B. K., & Baliarsinha, A. K. (2015) · Journal of the ASEAN Federation of Endocrine Societies · doi:10.15605/jafes.030.02.06 · Cited by 1 · see citing works
El-Rahman, A. A. A., El-Shafei, S., Shehab, G. M. G., Mansour, L. A., Abuelsaad, A. S. A., & Gad, R. A. (2023) · Life · doi:10.3390/life13091815 · Cited by 2 · see citing works
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Rueda, S. M. A., & Albarrán, L. Á. R. (2013) · Medunab · doi:10.29375/01237047.1763 · Cited by 1 · see citing works
贺, 福. (2013) · Scientia Sinica Vitae · doi:10.1360/052013-5
da Silva, J. C., & Ramos, H. E. (2014) · Revista de Ciências Médicas e Biológicas · doi:10.9771/cmbio.v12i4.9207
- Authors
- Cheung, C.-L., Lau, K.-S., Ho, A. Y. Y., Lee, K.-K., Tiu, S.-C., Lau, E. Y. F., Leung, J., Tsang, M.-W., Chan, K.-W., Yeung, C.-Y., Woo, Y.-C., Cheung, E. Y. N., Hung, V. H. F., Pang, H.-K., Hung, C.-S., Sham, P.-C., & Kung, A. W. C.
- Affiliations
- Queen Mary Hospital (CN)
- Tuen Mun Hospital (CN)
- Queen Elizabeth Hospital (CN)
- Pamela Youde Nethersole Eastern Hospital (CN)
- Ruttonjee Hospital (CN)
- United Christian Hospital (CN)
- Princess Margaret Hospital (HK)
- University of Hong Kong (HK)
- Corresponding author
- Cheung, Ching-Lung
- Sham, Pak-Chung
- Kung, Annie W C
- Venue
- Nature Genetics
- Published
- 2012-08-05
- Volume
- 44
- Issue
- 9
- Pages
- 1026-1029
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1979619099
- Cited by
- 41
- References
- 20
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 8 · 2013: 10
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- thyrotoxic periodic paralysis, thyrotoxicosis, KCNJ2, genetic susceptibility loci, Graves' disease, expression quantitative trait loci, potassium channel genes, Chinese population
- MeSH terms
- Kir5.1 Channel, Adult, Chromosomes, Human, Pair 17, Female, Genotype, Humans, Male, Paralyses, Familial Periodic, Thyrotoxicosis, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Quantitative Trait Loci, Asian People, Genome-Wide Association Study
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