HbA1c-Associated Novel Loci Identified by a Genome-Wide Association Study in Korean Cohorts

다국어 초록 (Multilingual Abstract)

HbA1c-Associated Novel Loci Identified by a Genome- Wide Association Study in Korean Cohorts Seogyun Jeong Convergence Biotechnology Department of Bioconvergence and Engineering Graduate School, Dankook University Advisor：Professor Sanghun Lee Background: Glycated hemoglobin (HbA1c) serves as a stable diagnostic marker for Type 2 diabetes, reflecting average blood glucose levels over approximately three months. HbA1c levels are influenced through glycemic pathways affecting blood glucose concentrations and erythrocytic pathways altering red blood cell properties. Family studies demonstrate that 55-75% of HbA1c variance is heritable. While genome-wide association studies (GWAS) in European and African populations have identified key loci such as GCK, MTNR1B, and G6PD, large-scale HbA1c GWAS in Korean populations still scarce. Methods: We performed a comprehensive GWAS of HbA1c in 36,086 Korean individuals from the Korean Genome and Epidemiology Study (KoGES), analyzing 7,104,316 SNPs after quality control. Independent association signals were identified through conditional analysis, and variants were classified as glycemic or erythrocytic based on associations with related traits and attenuation patterns. Novel loci were validated using Biobank Japan and MAGIC consortium summary statistics. Cross-ancestry comparisons were conducted with European, South Asian, African, and Hispanic populations to identify population-specific effects. Results: We identified 21 independent HbA1c-associated loci, including 19 previously reported variants and two novel loci: rs74384283 near TAS2R1 (P = 3.3 × 10⁻10) and rs79638982 near FAM102A (P = 3.81 × 10⁻8). Both novel variants were replicated in independent datasets and demonstrated glycemic mechanisms through phenome-wide association studies. The rs79638982 variant showed significant eQTL effects with LCN2 expression in pancreatic islets (Z = 3.826, P = 1.30 × 10⁻4), suggesting a biological pathway linking genetic variation to HbA1c regulation through LCN2. Cross-ancestry comparison revealed 14 variants with significant effect size heterogeneity (FDR < 0.05), with rs10908495 (GLMP) and rs12219514 (HHEX) showing consistently different effects across all four ancestry comparisons. Conclusions: This GWAS of 36,086 Korean individuals identified two novel HbA1c- associated loci (rs74384283 near TAS2R1 and rs79638982 near FAM102A) and 14 variants with ancestry-specific effect sizes. Functional analysis revealed rs79638982 upregulates LCN2 in pancreatic islets, implicating LCN2 in HbA1c regulation. These findings expand our understanding of HbA1c genetics and support ancestry-informed approaches to glycemic control

목차 (Table of Contents)

• 1. Introduction
• 1.1 Background of HbA1c 1
• 1.2 Previous studies 1
• 1.3 Study Aims 2
• 2. Methods
• 2.1 Study participants 3
• 2.2 Genotyping, Imputation and Quality Control 4
• 2.3 Genome-wide association study of HbA1c 4
• 2.4 Variant Classification and Replication Analysis 5
• 2.5 Variant visualization and Phenotypic Associations study 5
• 2.6 Functional annotation of novel Loci 6
• 2.7 Identification of East Asian-specific HbA1c variants 6
• 3. Results
• 3.1 Study population characteristics 8
• 3.2 Identification of genome-wide significant HbA1c-associated Loci 9
• 3.3 Novel loci across glycemic or erythrocytic traits and gene mapping 13
• 3.4 Comparison of HbA1c-associated variants between Korean and other ethnic populations 15
• 4. Discussion 16
• 5. Conclusion 19
• Reference 20