Genetic risk and polygenic risk score assessment of prediabetes and progression to type 2 diabetes

Aims: To identify susceptibility loci to prediabetes and evaluate the performance of existing polygenic risk scores (PGS) for type 2 diabetes (T2D) in predicting prevalent prediabetes and progression to diabetes. Materials and Methods: We conducted a case–control Genome-Wide Association Study (GWAS) on Qatar Biobank (QBB) participants with prediabetes (n = 2267) and normoglycaemia (n = 8665). We further evaluated the performance of 140 existing PGS for T2D in predicting prediabetes using logistic regression in the baseline QBB cohort (n = 10 932) and progression to T2D using Cox regression in the follow-up cohort (n = 2143). Results: GWAS identified two loci associated with prediabetes (p < 5 × 10⁻⁸), mapped near GCK and HK1 genes. Among 140 PGS, PGS004838 showed the strongest association with prediabetes (OR/SD: 1.37, 95% CI: 1.29–1.45, p-value: 4.45 × 10⁻²⁷). Among 2143 individuals without diabetes at baseline, 9.3% progressed to T2D over 6.0 years of median follow-up. PGS004838 outperformed the other 139 PGS in predicting progression to T2D (HR/SD: 1.79, 95% CI: 1.53–2.10, p-value: 2.08 × 10⁻¹³). Individuals in the very high genetic risk quintile were younger and had a 2.4-fold increased risk of progressing to T2D compared to the intermediate genetic risk quintile. Conclusions: This study identified two genetic loci associated with prediabetes. PGS004838 showed the highest performance in predicting prediabetes and progression to T2D, with the strongest effect reported to date. Our findings have clinical translation potential in risk stratification and early intervention.