Genetic liability to metabolic dysfunction modelled in early adulthood predicts cardiometabolic risk across the life course in Asian populations

Abstract Background: Cardiometabolic diseases arise from metabolic dysfunction that develops decades before clinical onset. Conventional genetic risk models are typically derived in middle-aged or older populations, where genetic effects are confounded by cumulative environmental exposures, chronic comorbidities, and clinical interventions. Whether the life stage at which genetic liability is modelled influences the biological signal captured by polygenic scores remains unclear, particularly in underrepresented populations. We therefore tested whether genetic liability modelled in early adulthood, a period of relative physiological stability, is associated with cardiometabolic risk across the life course in Asian populations. Methods: We developed a polygenic score for metabolic syndrome, GenMetS, using data from 1,368 Singaporean women aged 18-45 years. The model integrates 15 established polygenic scores for metabolic traits and applies elastic-net penalized regression to optimize variant weights. GenMetS was evaluated in five cohorts comprising 670,952 individuals aged 0-94 years across population-based and disease-enriched settings, including Asian and European ancestry groups. Associations with metabolic traits, cardiometabolic diseases, multimorbidity, and early-life growth patterns were assessed. Results: In Asian populations, GenMetS explained 5.0-12.4% of the variance in metabolic syndrome in adults and 10.3% in children, with negligible performance in European populations (R squared < 0.001). Higher GenMetS was associated with increased odds of cardiometabolic diseases, including type 2 diabetes, heart failure, and stroke (odds ratios 1.32-1.52 per standard deviation). In UK Biobank participants of Asian ancestry, GenMetS improved discrimination of cardiometabolic multimorbidity beyond age alone. Associations were consistent across sexes. In children, higher GenMetS was associated with obesogenic growth trajectories and increased abdominal adiposity. Conclusions: Genetic liability to metabolic dysfunction modelled in early adulthood captures a stable biological signal associated with metabolic traits, disease risk, and multimorbidity from childhood to adulthood in Asian populations. These findings indicate that the life stage of model derivation shapes the biological signal captured by polygenic scores and support the development of life-stage and ancestry-informed approaches for cardiometabolic risk assessment and prevention.