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Obesity Polygenic Risk and Healthy Lifestyle Interactions on Weight Trajectories in Women and Men.

Aishi Ghosh·Meghan Lau·Anika Fernandes·Brian E Cade·Elizabeth W Karlson·Susan Redline·Richa Saxena·Tianyi Huang·Hassan S Dashti
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Abstract

BACKGROUND: Genetics and environmental factors contribute to obesity risk, but the extent to which healthy behaviors can offset genetic susceptibility remains unclear. We examined the interaction between obesity polygenic risk and a composite healthy lifestyle score on body mass index (BMI) trajectories in women and men. METHODS: We analyzed 13&#x2009;780 women from the Nurses' Health Study and 8242 men from the Health Professionals Follow-Up Study, all of European ancestry and free of major chronic disease at baseline. The lifestyle score comprised American Heart Association Essential 8 components (nonsmoking, physical activity, healthy eating, adequate sleep) plus moderate alcohol intake, modeled as a time-varying variable. A genome-wide polygenic score for BMI was derived from genome-wide association study. Adjusted linear mixed-effects models estimated associations and interactions on biennial BMI measures over up to 26&#x2009;years. RESULTS: Each SD increase in the polygenic score was associated with 1.80&#x2009;kg/m2 (95% CI, 1.72-1.87) and 1.12&#x2009;kg/m2 (95% CI, 1.06-1.19) higher BMI in women and men, respectively. Significant interactions between the polygenic score and healthy lifestyle score (both P<0.05) showed a dose-response attenuation of the genetic effects with healthier lifestyles. Comparing the healthiest with the least healthy lifestyle groups, genetic effects on BMI were 35% lower in women and 28% lower in men. In sensitivity analyses, higher diet quality and physical activity consistently attenuated genetic associations in both cohorts, whereas current smoking showed similar effects in women only. CONCLUSIONS: Adherence to a healthier lifestyle attenuated the association between obesity polygenic risk and BMI in a dose-response manner.

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HumansFemaleObesityGenetic Risk ScoreBody Mass IndexHealthy LifestyleMaleMiddle AgedRisk FactorsAdultGenetic Predisposition to DiseaseGenome-Wide Association StudyExerciseDiet, HealthyRisk AssessmentAlcohol DrinkingUnited StatesSex FactorsBody WeightProspective StudiesBMIgenetic riskgene&#x2010;lifestyle interactionhealthy lifestyle scoreobesityobesogenic behaviorsJournal ArticleResearch Support, N.I.H., Extramural

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Aishi Ghosh, Meghan Lau, Anika Fernandes, Brian E Cade, Elizabeth W Karlson, Susan Redline, Richa Saxena, Tianyi Huang, Hassan S Dashti. 2026-06-23. Obesity Polygenic Risk and Healthy Lifestyle Interactions on Weight Trajectories in Women and Men.. https://doi.org/10.1161/jaha.126.049396

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