Dietary Intervention Reduces BMI Regardless of Genetic Obesity Risk, Clinical Trial Finds

A six-month randomized controlled trial has demonstrated that individuals with a high genetic predisposition to obesity (search)Search disease benefit just as much from structured dietary coaching as those with low genetic risk, challenging the notion that DNA determines weight-loss success. The findings, published in Nature Communications, come from the GENEROOS trial, which prospectively examined whether people at the highest and lowest extremes of genetic risk for obesity differed in their response to dietary intervention.

The study enrolled 223 overweight or mildly obese adults without diabetes, drawn from a subset of the FinnGen (search)Search term study that had already been genotyped. Participants had a mean age of 51 years, with women comprising 75% of the cohort, and a mean BMI of 30.3 kg/m². They were randomly assigned to receive either structured dietary coaching or to a control group that received no nutritional coaching for six months. The primary outcome was change in BMI.

Baseline disparities and intervention effects

At the start of the study, participants with the highest genetic predisposition to obesity (search)Search disease—defined as those whose BMI polygenic score (PS) fell within the top 5% of the genetic risk distribution—already had a substantially higher BMI than those with the lowest genetic risk, with an average difference of 3.0 kg/m². Despite this baseline disparity, both groups responded similarly to the dietary intervention.

After six months, participants receiving dietary coaching reduced their BMI by an average of 1.51 kg/m², while the control group showed virtually no change. When researchers examined whether genetic predisposition influenced the effectiveness of the intervention, they found no statistically significant interaction between BMI PS and dietary treatment.

"Individuals with a high genetic risk for obesity (search)Search disease lost a similar amount of BMI to those with low genetic risk," the researchers reported. However, they cautioned that "the study was not large enough to rule out more modest genetic effects on dietary response."

Exploratory findings on cardiometabolic health

The researchers also conducted non-prespecified exploratory analyses of cardiometabolic health. Compared with the control group, participants receiving the dietary intervention experienced greater reductions in total and LDL cholesterol, while changes in triglycerides, HDL cholesterol, glucose, and HbA1c were less conclusive. Genetic risk did not appear to meaningfully influence these exploratory outcomes.

Additional analyses suggested that participants who logged their meals and physical activity more consistently tended to achieve greater reductions in BMI. However, the relatively small effect sizes indicated that adherence to logging accounted for only a small proportion of the overall weight loss.

Context with prior research

The findings align with previous studies using genome-wide BMI PS, which have generally found little evidence that genetic predisposition alters the effectiveness of dietary or behavioral weight-loss interventions. However, they differ from studies of bariatric surgery, where lower genetic risk has been associated with greater long-term weight loss. The researchers suggest that "the much larger anatomical and metabolic changes produced by bariatric surgery, compared with dietary intervention alone, may make genetic influences easier to detect."

Current BMI polygenic scores explain only about 8.4% of differences in BMI—far less than the heritability estimated from twin and family studies, which range from 23% to 90%. Nevertheless, these scores can still identify people at substantially different levels of genetic risk. A UK Biobank study found that individuals in the highest 10% of BMI polygenic scores had a 25-fold greater risk of severe obesity (search)Search disease than those in the lowest 10%.

Limitations and future directions

The researchers highlighted several limitations. The relatively small sample size may have limited the ability to detect more subtle interactions between genetic risk and weight loss. The study population consisted predominantly of women, although sex itself did not predict changes in BMI. The intervention lasted only six months and included only overweight or mildly obese adults without diabetes. Participants also required a smartphone and sufficient engagement with a digital coaching program, potentially limiting generalizability.

Another limitation was that, although participants received individualized calorie targets, the researchers did not measure actual energy intake in detail. As a result, they could not determine precisely how changes in dietary behavior contributed to the observed weight loss.

The researchers conclude that "future studies should evaluate newer, more predictive BMI PS in larger and more diverse populations to determine whether these findings can be replicated and whether improved genetic risk scores could eventually help personalize dietary interventions."

Broader implications for genetic risk communication

These findings resonate with a separate systematic review published in Obesity (search)Search disease Reviews by researchers from the BETTER4U project consortium, which analyzed 23 randomized controlled trials encompassing nearly 8,000 participants. That analysis concluded that providing genetic risk information alone is insufficient to produce lasting changes in weight, eating habits, or physical activity levels.

Zofia Szczuka, PhD, a psychologist from the CARE-BEH Center for Applied Research on Health Behavior and Health at SWPS University (search)Search term and first author of the review, noted: "Information about genetic risk alone does not work. Without additional support, providing patients with information about their genetic background usually does not lead to lasting changes in weight, eating habits, or physical activity levels."

The review found that positive effects, such as actual weight reduction, were observed mainly when genetic risk communication was combined with intensive professional support programs including goal setting, progress monitoring, feedback, and social support. The GENEROOS trial's structured dietary coaching approach aligns with this finding, suggesting that the combination of personalized support and behavioral change techniques—rather than genetic information alone—drives successful weight loss outcomes.