Genome-wide meta-analysis reveals novel susceptibility loci for thyrotoxic periodic paralysis.

Autor:	Hoi-Yee Li G; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.; Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong., Cheung CL; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong., Zhao SX; Department of Molecular Diagnostics, The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China., Song HD; Department of Molecular Diagnostics, The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiaotong University School of Medicine, Shanghai, China., Wai-Chee Kung A; Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2020 Dec; Vol. 183 (6), pp. 607-617.
DOI:	10.1530/EJE-20-0523
Abstrakt:	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.
Databáze:	MEDLINE
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