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Polygenic risk score for type 2 diabetes shows context-dependent effects across populations
Boya Guo1, Yanwei Cai2, Daeeun Kim3,4
1Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. bguo@fredhutch.org.
Nature Communications
|October 1, 2025
Summary
Polygenic risk scores can predict type 2 diabetes risk, but performance varies by population and individual factors. These scores also link to diabetes complications and shared genetic traits.
Area of Science:
- Genetics
- Epidemiology
- Precision Medicine
Background:
- Polygenic risk scores (PRS) show prognostic value for type 2 diabetes (T2D).
- Generalizability of T2D PRS across diverse populations requires further investigation.
- Understanding PRS performance in varied contexts is crucial for clinical application.
Purpose of the Study:
- To systematically characterize a multi-ancestry T2D PRS.
- To evaluate T2D PRS performance and generalizability across diverse populations and contexts.
- To explore associations between T2D PRS and cardiometabolic traits and T2D complications.
Main Methods:
- Systematic characterization of a T2D PRS using data from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks/cohorts.
- Analysis included 244,637 T2D cases and 637,891 controls.
- Evaluation of PRS performance across diverse demographic and clinical subgroups.
Main Results:
- T2D PRS performance is context-dependent, showing better utility in younger, male, and non-obese individuals without hypertension.
- The T2D PRS is associated with cardiometabolic traits and T2D complications.
- Differential performance in T2D prediction across populations was observed, yet associations with related traits were generalizable.
Conclusions:
- Contextual factors significantly influence T2D PRS performance for risk prognostication.
- T2D PRS demonstrates potential for stratifying risk of complications and identifying shared genetic architecture.
- Comprehensive characterization is needed to optimize T2D PRS utility in diverse populations.
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