Physical Activity and Incident Obesity Across the Spectrum of Genetic Risk for Obesity

Abstract

Importance: Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic variability, increasing risk of obesity.

Objective: To use activity, clinical, and genetic data from the All of Us Research Program (AoURP) to explore the association of genetic risk of higher body mass index (BMI) with the level of physical activity needed to reduce incident obesity.

Design, setting, and participants: In this US population-based retrospective cohort study, participants were enrolled in the AoURP between May 1, 2018, and July 1, 2022. Enrollees in the AoURP who were of European ancestry, owned a personal activity tracking device, and did not have obesity up to 6 months into activity tracking were included in the analysis.

Exposure: Physical activity expressed as daily step counts and a polygenic risk score (PRS) for BMI, calculated as weight in kilograms divided by height in meters squared.

Main outcome and measures: Incident obesity (BMI ≥30).

Results: A total of 3124 participants met inclusion criteria. Among 3051 participants with available data, 2216 (73%) were women, and the median age was 52.7 (IQR, 36.4-62.8) years. The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5.4 (IQR, 3.4-7.0) years of personal activity tracking. The incidence of obesity over the study period increased from 13% (101 of 781) to 43% (335 of 781) in the lowest and highest PRS quartiles, respectively (P = 1.0 × 10-20). The BMI PRS demonstrated an 81% increase in obesity risk (P = 3.57 × 10-20) while mean step count demonstrated a 43% reduction (P = 5.30 × 10-12) when comparing the 75th and 25th percentiles, respectively. Individuals with a PRS in the 75th percentile would need to walk a mean of 2280 (95% CI, 1680-3310) more steps per day (11 020 total) than those at the 50th percentile to have a comparable risk of obesity. To have a comparable risk of obesity to individuals at the 25th percentile of PRS, those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d; with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and with a baseline BMI of 28, an additional 6350 steps/d.

Conclusions and relevance: In this cohort study, the association between daily step count and obesity risk across genetic background and baseline BMI were quantified. Population-based recommendations may underestimate physical activity needed to prevent obesity among those at high genetic risk.

Figure 1.. Risk of Incident Obesity Modeled by Mean Daily Step Count and Polygenic Risk Scores (PRSs)

Hazard ratio for obesity was modeled according to mean daily step counts and 25th, 50th, and 75th percentile PRS for body mass index. Shaded regions represent 95% CIs. Model is adjusted for age, sex, mean baseline step counts, cancer status, coronary artery disease status, systolic blood pressure, alcohol use, educational level, and a PRS × mean steps interaction term.

Figure 2.. Associations Between Model Components and Hazard Ratio (HR) of Obesity

Mean daily steps and polygenic risk score (PRS) for higher body mass index are independently associated with hazard for obesity. Hazard ratios model the difference between the 75th and 25th percentiles for continuous variables. CAD indicate coronary artery disease; and SBP, systolic blood pressure.

Figure 3.. Risk of Incident Obesity Based on Mean Daily Steps and Polygenic Risk Score (PRS) Percentile Stratified by Baseline Body Mass Index (BMI)

Each point estimate is indexed to a hazard ratio for obesity of 1.00 (BMI [calculated as weight in kilograms divided by height in meters squared] ≥30). Error bars represent 95% CIs.

Figure 4.. Cumulative Risk of Incident Obesity by Polygenic Risk Score (PRS) and Mean Daily Step Count at Years 1, 3, and 5