Assessment of Molecular Subtypes in Thyrotoxic Periodic Paralysis and Graves Disease Among Chinese Han Adults

Abstract

Key Points Question Is thyrotoxic periodic paralysis (TPP) a molecular subtype of Graves disease? Findings In this case-control study in a Chinese Han population, 5 TPP susceptibility loci were identified, including 3 specific loci and 2 loci shared by Graves disease and TPP. The ratio of persistent thyrotropin receptor antibody positivity was higher in TPP than in Graves disease, and TPP could be predicted from Graves disease using TPP-specific loci. Meaning A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP, suggesting TPP as a molecular subtype of Graves disease.

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

“…Fine mapping identified a single variant (rs9501257, PPA > 0.99) as likely causal for both genetic signals, associated with increased HLA-DPA2 expression (effect size b = 1.08; Table S3) and located in the 3 0 UTR of the neighboring HLA-DPB1 gene. This variant is in moderate LD with a hepatitis B infection GWAS SNP (rs3128923, R 2 = 0.47 in Africans) and is in high Dʹ (Dʹ = 1 in multiple populations) with variants associated with liver cancer following hepatitis B infection (rs2295119) and autoimmune diseases (rs2295119 and rs2281388: immunoglobulin A glomerulonephritis and Graves' disease) (Chu et al, 2011;Li et al, 2020;Sawai et al, 2018;Zeng et al, 2021;Zhao et al, 2019). These data suggest increased expression of HLA-DPA2 in the cerebellum is causally associated with COVID-19 disease severity.…”

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

“…We previously identified mutations in an unreported gene, potassium inwardly rectifying channel subfamily J member 18 (KCNJ18) encoding the inwardly rectifying potassium (KIR) channel KIR2.6, were present in approximately one-third of TPP patients (4). On the other hand, using genome-wide association study (GWAS), we identified another member of KIR channels, KCNJ2, as a susceptibility gene of TPP, and significant association with KCNJ2 was consistently observed in other GWAS of TPP (5,6,7). In the latest single-cohort GWAS, a novel genome-wide significant TPP locus unrelated to ion channel was revealed in dachsous cadherin-related 2 (DCHS2) (7).…”

“…On the other hand, using genome-wide association study (GWAS), we identified another member of KIR channels, KCNJ2, as a susceptibility gene of TPP, and significant association with KCNJ2 was consistently observed in other GWAS of TPP (5,6,7). In the latest single-cohort GWAS, a novel genome-wide significant TPP locus unrelated to ion channel was revealed in dachsous cadherin-related 2 (DCHS2) (7). In addition to the loci near KCNJ2 and a suggestive locus near C11orf67, the three susceptibility loci contributed to 3.1% heritability of the disease (7) but they could not fully explain the genetic liability of TPP.…”

“…In the latest single-cohort GWAS, a novel genome-wide significant TPP locus unrelated to ion channel was revealed in dachsous cadherin-related 2 (DCHS2) (7). In addition to the loci near KCNJ2 and a suggestive locus near C11orf67, the three susceptibility loci contributed to 3.1% heritability of the disease (7) but they could not fully explain the genetic liability of TPP.…”

“…In the present study, we aimed to dissect the genetics of TPP by firstly performing an additional GWAS in a southern Chinese cohort in Hong Kong with 92 TPP cases and 2077 controls, then conducted a meta-analysis with two published GWAS (7,8), totaling 319 TPP cases and 3516 healthy controls. To enhance early identification of the disease, the TPP-associated genetic variants derived from the meta-analysis were employed to develop a weighted genetic risk score (GRS).…”