Polygenic risk scores, adiposity, and disease transition in type 2 diabetes and colorectal cancer comorbidity: a population-based Chinese cohort study

Abstract Background The co-occurrence of type 2 diabetes (T2D) and colorectal cancer (CRC) represents an increasing public health concern, contributing to greater clinical complexity and poorer outcomes. This study aimed to evaluate whether polygenic risk scores (PRS) for T2D and CRC are associated with the risk of T2D–CRC comorbidity and to investigate their potential interaction with body mass index (BMI). Methods A Chinese cohort comprising four groups was analyzed, including individuals with both T2D and CRC (n = 202), T2D only (n = 203), CRC only (n = 199), and controls (n = 201). Ancestry-matched genome-wide association study data were used to construct PRS for T2D and CRC. Associations between genetic risk, adiposity, and disease status were assessed using multinomial logistic regression and multi-state models. Results Individuals with T2D–CRC comorbidity exhibited higher PRS for both T2D and CRC compared with controls. Multinomial regression showed that T2D PRS was positively associated with CRC risk ( OR = 1.24, P = 0.046). BMI significantly modified the association between CRC genetic liability and isolated CRC risk ( OR = 1.75, 95% CI : 1.27–2.34), with stronger associations observed among overweight individuals ( P for interaction = 0.033). Multi-state modeling further suggested a directional pattern in disease progression, where CRC genetic liability was associated with an increased likelihood of transition to comorbidity among individuals with pre-existing T2D ( HR = 1.21, P = 0.037). Notably, individuals in the high CRC PRS group (≥75th percentile) demonstrated a substantially higher cumulative probability of progressing to comorbidity, reaching approximately 72.2% by age 80, compared with those in the low genetic risk group. Conclusions Genetic susceptibility to both T2D and CRC, together with adiposity, may help identify individuals at higher risk of developing comorbidity. Integrating PRS with BMI may provide a useful approach for risk stratification and support targeted prevention strategies in populations at elevated risk.