Dietary intervention and BMI reduction in individuals at the extremes of genetic predisposition to higher BMI: a randomized controlled trial

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Genetic susceptibility substantially contributes to inter-individual variation in body mass index (BMI), yet it remains unclear whether genome-wide polygenic risk modifies response to dietary weight loss interventions. We conducted a prospective, randomized controlled trial (GENEROOS) to test whether a BMI polygenic score (PS) interacts with a six-month dietary intervention on BMI change, which was the primary outcome. Using a genetic-first recontact strategy within 38,621 genotyped individuals, we recruited overweight or mildly obese, non-diabetic adults from the top and bottom 5% of the BMI PS distribution. A total of 223 participants (mean age 51.1 years; 74.9% women; mean BMI 30.3 kg/m²) were randomized to structured dietary coaching or control. At baseline, individuals in the top 5% of the BMI PS distribution had a BMI 3.0 kg/m² higher than those in the bottom 5%. The diet intervention reduced BMI at six months (-1.51 kg/m², 95% CI - 1.72 to -1.31) compared with controls (-0.01 kg/m², 95% CI - 0.22 to 0.19). However, we observed no evidence of a BMI PS by intervention interaction on BMI change (β = 0.06, 95% CI - 1.33 to 1.44; P = 0.94). These findings suggest that, in this population, genetic susceptibility to higher BMI, as captured by current genome-wide polygenic scores, does not substantially modify short-term weight loss response to dietary intervention. However, given the study's sample size, modest interaction effects cannot be excluded, and larger studies are needed to clarify the role of polygenic scores in stratifying lifestyle-based weight loss interventions. ClinicalTrials.gov Identifier NCT06092372.

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