Mechanistic Heterogeneity in Type 2 Diabetes and Hypertension Comorbidity Revealed with Partitioned Polygenic Scores

Type 2 diabetes (T2D) and hypertension are common health conditions that often occur together, suggesting shared biological mechanisms. To explore this relationship, we analysed large-scale multiomic data to uncover genetic factors underlying T2D and blood pressure (BP) comorbidity. We curated 1,304 independent single-nucleotide variants (SNVs) associated with T2D/BP, grouping them into five clusters related to metabolic syndrome, inverse T2D-BP risk, impaired pancreatic beta-cell function, higher adiposity, and vascular dysfunction. Colocalisation with tissue-specific gene expression highlighted significant enrichment in pathways related to thyroid function and fetal development. Partitioned polygenic scores (PGS) derived from these clusters improved risk prediction for T2D-hypertension comorbidity, identifying individuals with more than twice usual susceptibility. These results reveal complex genetic basis of shared T2D and BP mechanistic heterogeneity, enhancing comorbidity risk prediction. Partitioned PGSs offer promising approach for early risk stratification, personalised prevention, and improved management of these interconnected conditions, supporting precision medicine and public health initiatives.