# Partitioned polygenic scores show mechanistic heterogeneity in type 2 diabetes and hypertension comorbidity

## TL;DR

This study finds that type 2 diabetes and hypertension share diverse genetic factors, which can improve risk prediction and personalized prevention strategies.

## Contribution

The study introduces partitioned polygenic scores to reveal mechanistic heterogeneity in type 2 diabetes and hypertension comorbidity.

## Key findings

- Genetic variants are grouped into five clusters related to distinct biological processes like metabolic syndrome and vascular dysfunction.
- Partitioned polygenic scores improve risk prediction for comorbidity, identifying individuals with over twice the usual susceptibility.
- Colocalization analysis highlights enrichment in pathways related to thyroid function and fetal development.

## Abstract

Type 2 diabetes and hypertension are common health conditions that often occur together, suggesting shared biological mechanisms. To explore this relationship, we analyse large-scale multiomic data to uncover genetic factors underlying type 2 diabetes and blood pressure comorbidity. We curate 1304 independent single-nucleotide variants associated with type 2 diabetes and blood pressure, grouping them into five clusters related to metabolic syndrome, inverse type 2 diabetes/blood pressure risk, impaired pancreatic beta-cell function, higher adiposity, and vascular dysfunction. Colocalization with tissue-specific gene expression highlights significant enrichment in pathways related to thyroid function and fetal development. Partitioned polygenic scores derived from these clusters improve risk prediction for type 2 diabetes/hypertension comorbidity, identifying individuals with more than twice the usual susceptibility. These results reveal a mechanistically heterogeneous genetic architecture shared between type 2 diabetes and blood pressure, enhancing comorbidity risk prediction. Partitioned polygenic risk scores offer a promising approach for early risk stratification, personalised prevention, and improved management of these interconnected conditions.

Type 2 diabetes and hypertension often co-occur, suggesting shared biological mechanisms. Here, Pascat et al. use partitioned polygenic scores to show distinct biological processes link both conditions and improve risk prediction.