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.

The predisposition to thyrotoxic periodic paralysis (TPP) is due to a genetic variant in the inward‐rectifying potassium channel, KCNJ2

“…The KCNJ2 gene encodes a potassium inwardly rectifying channel, subfamily J, member 2 (Kir2·1), which allows potassium influx. Their findings were also supported by another GWAS . In this study, we conducted a case–control analysis to replicate the GWAS study in a Hong Kong population.…”

“…Candidate gene studies targeting ion channel genes important in skeletal muscle, such as CACNA1S , SCN4A , KCNE3 and KCNJ18, have been performed, but results have not been conclusive . Only recently, the susceptibility locus for TPP on chromosome 17q24.3 near KCNJ2 gene has been revealed by genome‐wide association studies (GWAS) …”

Genetically induced dysfunctions of Kir2.1 channels: implications for short QT3 syndrome and autism–epilepsy phenotype

“…As Kir2 channels, together with Kir4.1 and Kir5.1, contribute to regulate neuronal excitability, cell differentiation, synaptic plasticity and wiring, their dysfunction may impact these crucial neurophysiological processes and result in functional impairment of neural networks (further discussed in 11,12; 42–44). The clinical findings and mechanistic insights provided here, combined with recent studies showing the presence of neuropsychiatric disorders in individuals with mutations in KCNJ2 (2,4–6), indicate a possible role of the Kir2.1 channels in the pathogenesis of autism–epilepsy. Given that most ASD behave as a complex multigenic disorder, Kir2.1 dysfunction in limbic neurons and astrocytes may enhance susceptibility to the disease when other contributing alleles (including KCNJ10 , as in our probands) are co-inherited.…”

“…The disease is linked to a loss of function of Kir2.1 channels (3). Individuals harboring mutations in KCNJ2 may also present mood disorders and seizures (4–6). Notably, seizure susceptibility associated with cardiac arrhythmia have been described in several K + channelepsies that may increase the risk to sudden unexpected death in affected patients (7).…”

The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis

“…During the genotyping and matching of our cohort of TPP and controls (TWP) for ABCC8 variant, two Asian GWAS studies were published, indicating that a new TPP locus (17q24.3) has emerged (Cheung et al 2012, Jongjaroenprasert et al 2012. None of the genes related to insulin response is found within this locus, indicating that ABCC8 hyperinsulinaemia genetic predisposition is either an additional phenotype-modulating trait or an ethnic-dependent linked genetic association.…”