Effect of a Dietary Intervention on Weight Loss in Adults with High vs Low Genetic Predisposition to Higher BMI: A Randomized Diet Intervention Trial

It is unclear whether the effectiveness of weight loss interventions differs based on genetic predisposition to higher body mass index (BMI). Genome-wide polygenic scores (PS) for BMI are the strongest genetic predictors of elevated body weight, but no prospective trials have evaluated weight loss responses based on BMI PS. To assess whether adults with high or low genetic predisposition to higher BMI experience differential weight loss during a 6-month dietary intervention, we designed the GENEROOS study, a single-site, randomised controlled trial conducted in Finland from October 2023 to November 2024. Participants (N=223), aged 30–65 years, with a BMI of 23–36 kg/m² and no diabetes, were recruited from 38,621 genotyped individuals in the Finnish Clinical Biobank Tampere. They were selected from the top or bottom 5th percentile of the BMI PS distribution and randomized to either a six-month dietary coaching program aimed at a 500 kcal/day energy deficit or to a control group receiving no dietary intervention. The main outcome was change in body weight (%) from baseline to 6 months and the interaction between BMI PS and intervention status. At baseline, those in the top 5% of BMI PS weighed on average 8.4 kg (95% CI, 5.1 to 11.7 kg) more than those in the bottom 5%. In the intervention group, mean weight change at 2, 4, and 6 months was −3.89%, −5.32%, and −4.70%; in the control group it was −1.10%, −0.85%, and 0.14%, respectively. No significant interaction was found between BMI PS and intervention on weight change (β = 0.06 [95% CI, −1.33 to 1.44]; P = .94). In this randomised trial, genetic predisposition as measured by BMI PS did not modify response to dietary intervention, indicating that leveraging polygenic scores may not enhance the effectiveness of personalized weight loss strategies.