Exploring functional genetic variants underlying hyperthyroidism and hypothyroidism in a Korean population

Purpose: Thyroid dysfunction, including hyperthyroidism and hypothyroidism, significantly impacts metabolism and development.While genetic factors contribute substantially to thyroid function, gene-gene interactions and polygenic architecture remain inadequately explored, particularly in Korean populations.To investigate genetic variants underlying hyperthyroidism and hypothyroidism, emphasizing gene-gene interactions and polygenic risk modeling in a Korean cohort.Materials and Methods: Using the KoGES (Korean Genome and Epidemiology Study) HEXA (Health Examinees) cohort, we analyzed 842 hyperthyroidism cases, 870 hypothyroidism cases, and 38,798 controls aged.Following quality control and logistic regression analysis, single nucleotide polymorphisms (SNPs) were refined through linkage disequilibrium (r<0.4) and literature curation.Functional annotations using RegulomeDB and GTEx Portal assessed regulatory potential and tissuespecific effects.Generalized multifactor dimensionality reduction (GMDR) identified optimal gene-gene interaction models, validated through genetic risk scores (GRS) and protein-protein interaction network analysis.Results: We identified 5 SNPs for hyperthyroidism and 12 for hypothyroidism, predominantly clustered in chromosome 6 human leukocyte antigen (HLA) regions.RegulomeDB analysis revealed most SNPs had 1d-1f scores indicating high regulatory potential, while GTEx analysis confirmed these variants had stronger effects on RNA splicing than total gene expression.Optimal GMDR models included 2-3 SNP combinations for hyperthyroidism and 4-6 SNP combinations for hypothyroidism.GRS models demonstrated clear dose-response relationships, with high-risk groups showing 2.12-fold (hyperthyroidism) and 2.64-fold (hypothyroidism) increased disease risk. Conclusion:This study reveals Korean-specific polygenic architecture underlying thyroid dysfunction, personalized risk assessment and precision medicine approaches in Korean populations.