Polygenic risk scores for cluster of newly diagnosed type 2 diabetes: genetic insights and clinical implications

Type 2 diabetes (T2D) is a heterogeneous disease that can be distinguished at newly diagnosis by variations in clinical presentation, disease trajectory, therapeutic response, and risk of complications. Its global prevalence is increasing, particularly among Asian populations such as Thais, due to unique genetic and environmental factors. Thai patients with newly diagnosed T2D have been classified into four clusters based on standard clinical parameters. However, the polygenic basis underlying these distinct phenotypes remains unclear. In this study, we investigated the association between polygenic risk score (PRS) models and T2D in 680 Thai participants. Of these, 487 were T2D patients in four clusters, and 193 were nondiabetic controls. Genotyping was performed, and we calculated PRS models using data from the PGScatalog. Five PRS models significantly differentiated T2D from controls, with PGS000804 displaying the strongest predictive power. Two PRS models (PGS000804 and PGS003402) showed an inverse correlation with age at diagnosis. Moreover, eight genetic loci (rs2216063, rs9358356, rs9472138, rs6479591, rs4382480, rs189339, rs10818763, rs3132469) were significantly associated with both T2D and age at diagnosis. Among these loci, the alternative allele of rs2216063 (G/A), rs9358356 (T/C), and rs9472138 (C/T) conferred a lower T2D risk and were positively associated with older age at diagnosis. Individuals with the GTC/GTC genotype at these three loci developed diabetes approximately 10 years earlier than those with other genotypes. Our findings underscore the utility of PRS models in refining T2D subtypes and promoting precision medicine in the Thai population.