# Impact of Genetic Predisposition to Obesity on Long‐Term Maintenance of Modest Weight Loss in Postmenopausal Women

## TL;DR

This study shows that genetic risk for obesity may predict how well postmenopausal women maintain weight loss over time, especially in European Americans.

## Contribution

The study reveals that high genetic risk for obesity is linked to faster weight regain after modest weight loss in European American women.

## Key findings

- European American women with high PRSBMI regained nearly twice as much weight annually after intervention intensity decreased.
- No significant association was found between PRSBMI and weight regain in African American women.
- The results suggest ancestry-specific variability in how genetic risk influences weight maintenance.

## Abstract

Long‐term weight regain limits the population‐level benefits of obesity interventions. We tested whether the polygenic risk score of BMI (PRSBMI) modifies weight trajectories following modest weight loss.

The analytic sample included 9897 postmenopausal women from the Women's Health Initiative Dietary Modification Trial (6132 European American; 3749 African American). PRSBMI was derived from a trans‐ancestry GWAS of ~2 million participants. Longitudinal weight change (7 years) was modeled using weighted GEE.

In European Americans, the PRSBMI × randomization × time interactions approached significance at the 95th percentile (p = 0.052) and 85th percentile (p = 0.07). No interaction was observed in African Americans. In analyses restricted to European Americans who lost ≥ 5% of initial weight by year 1 (20%; n = 1273), women in the ≥ 95th percentile of PRSBMI regained nearly twice as much per year as those with average risk (0.94 vs. 0.48 kg/year, p = 0.0016).

A high PRSBMI was associated with faster weight regain following modest weight loss in European American women. While further validation is required in a diverse population, these results suggest the potential for genetics to inform targeted strategies for sustaining long‐term weight management.

ClinicalTrials.gov identifier: 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005

What is already known?○Initial weight loss is frequently followed by long‐term weight regain.○Recent polygenic risk scores (PRS) for obesity derived from large‐scale genetic studies, which account for approximately 5%–10% of the variation in BMI, provide increasingly actionable information for prevention.○The role of genetic risk in shaping long‐term outcomes after modest diet‐induced weight loss remains unclear.
What does this study add?○Among 1273 European American women who reached ≥ 5% weight loss by year 1 under high‐intensity intervention (18 sessions/year), those in the top 5% of PRSBMI regained 0.94 kg annually once intervention frequency decreased (4 sessions/year), which is nearly double of 0.48 kg annual regain by women at normal to low risk.○No similar association was observed among 453 African American women who achieved ≥ 5% weight loss by year 1, which suggests ancestry‐specific variability in the predictive performance of PRSBMI.
How might these results change the direction of research or the focus of clinical practice?○The impact of high PRSBMI on accelerated weight regain may be mediated by homeostatic counter‐regulation, which warrants further investigation.○Clinically, a PRSBMI may help stratify patients for tailored weight management, including adjunct pharmacotherapy or behavioral support after initial weight loss.

What is already known?○Initial weight loss is frequently followed by long‐term weight regain.○Recent polygenic risk scores (PRS) for obesity derived from large‐scale genetic studies, which account for approximately 5%–10% of the variation in BMI, provide increasingly actionable information for prevention.○The role of genetic risk in shaping long‐term outcomes after modest diet‐induced weight loss remains unclear.

Initial weight loss is frequently followed by long‐term weight regain.

Recent polygenic risk scores (PRS) for obesity derived from large‐scale genetic studies, which account for approximately 5%–10% of the variation in BMI, provide increasingly actionable information for prevention.

The role of genetic risk in shaping long‐term outcomes after modest diet‐induced weight loss remains unclear.

What does this study add?○Among 1273 European American women who reached ≥ 5% weight loss by year 1 under high‐intensity intervention (18 sessions/year), those in the top 5% of PRSBMI regained 0.94 kg annually once intervention frequency decreased (4 sessions/year), which is nearly double of 0.48 kg annual regain by women at normal to low risk.○No similar association was observed among 453 African American women who achieved ≥ 5% weight loss by year 1, which suggests ancestry‐specific variability in the predictive performance of PRSBMI.

Among 1273 European American women who reached ≥ 5% weight loss by year 1 under high‐intensity intervention (18 sessions/year), those in the top 5% of PRSBMI regained 0.94 kg annually once intervention frequency decreased (4 sessions/year), which is nearly double of 0.48 kg annual regain by women at normal to low risk.

No similar association was observed among 453 African American women who achieved ≥ 5% weight loss by year 1, which suggests ancestry‐specific variability in the predictive performance of PRSBMI.

How might these results change the direction of research or the focus of clinical practice?○The impact of high PRSBMI on accelerated weight regain may be mediated by homeostatic counter‐regulation, which warrants further investigation.○Clinically, a PRSBMI may help stratify patients for tailored weight management, including adjunct pharmacotherapy or behavioral support after initial weight loss.

The impact of high PRSBMI on accelerated weight regain may be mediated by homeostatic counter‐regulation, which warrants further investigation.

Clinically, a PRSBMI may help stratify patients for tailored weight management, including adjunct pharmacotherapy or behavioral support after initial weight loss.