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

[Objectives] To discover susceptibility loci of thyrotoxic periodic paralysis (TPP) by meta-analysis of genome-wide association study (GWAS). [Methods] This meta-analysis comprised 319 TPP cases and 3,516 healthy controls of Chinese ethnicity from three independent cohorts (two from Hong Kong and one from Shanghai). Genetic variants in each cohort were separately genotyped, imputed using the Haplotype Reference Consortium reference panel, and analyzed for association with TPP with adjustment for principal components. The results were meta-analyzed using fixed-effect inverse variance-weighted method. The genome-wide significant independent variants identified were employed to develop a weighted genetic risk score. Functionality of the susceptibility variants were examined. [Results] Of the 7,108,718 variants tested for association with TPP, 260 variants reached genome-wide significance (p<5E-8) and were represented by four independent variants from four distinct genomic loci. Excluding 6p21.33-p21.22 representing a risk locus for Graves disease and 17q24.3 near KCNJ2 which was previously reported, two novel loci near TRIM2 (4q31.3; rs6827197: OR=4.08; P=3.51E-9) and AC140912.1 (16q22.3; rs6420387: OR=1.86; P=2.71E-8) were identified. Together with KCNJ2 (rs312743: OR=2.56; P=5.15E-21), these three independent susceptibility variants explained 4.36% of the variance. The weighted genetic risk score based on three variants had an area under curve of 0.827 and 0.682 in the derivation and validation cohorts in Hong Kong. The variants might contribute to disease pathogenesis by altering expression of TRIM2 at tibial nerve and KCNJ2 in skeletal muscles. Notably, rare mutations in both TRIM2 and KCNJ2 were implicated in monogenic disorders characterized by muscle paralysis. [Conclusions] We identified two novel TPP risk loci near TRIM2 and AC140912.1. Future replication studies are warranted to confirm present findings.