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Title: | Genome-wide meta-analysis reveals novel susceptibility loci for thyrotoxic periodic paralysis | Authors: | Li, GHY Cheung, CL Zhao, SX Song, HD Kung, AWC |
Issue Date: | 2020 | Source: | European journal of endocrinology, 2020, v. 183, no. 6, p. 607-617 | Abstract: | Objective: Thyrotoxic periodic paralysis (TPP) is a rare and potentially fatal complication of hyperthyroidism. By meta-analysis of genome-wide association studies, we aim to discover novel susceptibility loci and understand the pathogenesis of TPP. Methods: This meta-analysis comprised 319 TPP cases and 3516 healthy controls from three independent cohorts (two from Hong Kong; one from Shanghai). Genetic variants in each cohort were separately genotyped, imputed and analyzed for association with TPP. Fixed-effect meta-analysis was performed to combine the data. Using the three independent genome-wide significant variants, a weighted genetic risk score (GRS) was developed. Results: Of 7 077 246 variants tested for association with TPP, 260 variants reached genome-wide significance and were represented by independent variants from four distinct genomic loci, but a risk locus for Graves' disease at 6p21.33-p21.22 was excluded from subsequent analyses. Two novel loci near TRIM2 (4q31.3; rs6827197: OR = 4.075; P = 3.46 × 10−9) and AC140912.1 (16q22.3; rs6420387: OR = 1.861; P = 2.66 × 10−8) were identified. Together with previously reported KCNJ2 (17q24.3; rs312743: OR = 2.564; P = 1.15 × 10−21), the three susceptibility variants explained 4.36% of the genetic liability. Expression quantitative trait loci analyses showed the variants altered expression of TRIM2 in nerve and KCNJ2 in skeletal muscle. The weighted GRS had an area under curve of 0.827 and 0.682 in the derivation and validation cohorts in Hong Kong. Conclusions: We identified two novel TPP risk loci near TRIM2 and AC140912.1. While rare mutations in TRIM2 and KCNJ2 were implicated in monogenic disorders characterized by muscle paralysis, our study suggested common variants near these genes might dysregulate gene expression and lead to milder phenotypes. |
Keywords: | Thyrotoxic periodic paralysis Genome-Wide association studies Meta-Analysis Genetic risk score |
Publisher: | BioScientifica | Journal: | European journal of endocrinology | ISSN: | 0804-4643 | EISSN: | 1479-683X | DOI: | 10.1530/EJE-20-0523 | Rights: | © 2020 European Society of Endocrinology Disclaimer: this is not the definitive Version of Record of this article. This manuscript has been accepted for publication in European Journal of Endocrinology, but the version presented here has not yet been copy-edited, formatted or proofed. Consequently, Bioscientifica accepts no responsibility for any errors or omissions it may contain.The definitive version is now freely available at https://doi.org/10.1530/EJE-20-0523, 2020 |
Appears in Collections: | Journal/Magazine Article |
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File | Description | Size | Format | |
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TPPMetaAnalysis_Manuscript_EurJEndo_R2_Final_Clean.pdf | Pre-Published version | 1.24 MB | Adobe PDF | View/Open |
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