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Polygenic Risk, Fitness, and Obesity in the CARDIA Study
Study Questions:
What is the relative importance of polygenic risk scores (PRS), fitness, activity, parental history of overweight, and body mass index (BMI) in young adulthood on BMI trends over 25 years?
Methods:
The CARDIA investigators conducted a population-based prospective cohort study at four US centers, which included white individuals and black individuals with assessments of polygenic risk of obesity, fitness, activity, and BMI in young adulthood (in their 20s) and up to 25 years of follow-up. Data collected between March 1985 and August 2011 were analyzed from April 25, 2019, to September 29, 2019. The main outcomes measure was BMI at the initial visit and 25 years later. For the final generalized models for BMI at each time point, the total cumulative variance explained by all predictors (standard clinical variables, as well as fitness, activity, and/or the PRS [with ancestry expressed as 10 principal components]) was computed, as were β coefficients per standard deviation (SD) in each predictor variable (e.g., how much is BMI expected to increase per SD increase in the PRS?).
Results:
This study evaluated an obesity PRS from a recently reported study of 1,608 white individuals (848 women [52.7%]) and 909 black individuals (548 women [60.3%]) across the United States. At baseline (year 0), mean (SD) overall BMI was 24.2 (4.5), which increased to 29.6 (6.9) at year 25. Among white individuals, the PRS (combined with age, sex, self-reported parental history of overweight, and principal components of ancestry) explained 11.9% (at year 0) and 13.6% (at year 25) of variation in BMI. Although the addition of fitness increased the explanatory capability of the model (24.0% variance at baseline and up to 18.1% variance in BMI at year 25), baseline BMI in young adulthood was the strongest factor, explaining 52.3% of BMI in midlife in combination with age, sex, and self-reported parental history of overweight. Accordingly, models that included baseline BMI (especially BMI surveillance over time) were better in predicting BMI at year 25 compared with the PRS. In fully adjusted models, the effect sizes for fitness and the PRS on BMI were comparable in opposing directions. The added explanatory capacity of the PRS among black individuals was lower than among white individuals. Among white individuals, addition of baseline BMI and surveillance of BMI over time was associated with improved precision of predicted BMI at year 25 (mean error in predicted BMI, 0 kg/m2; 95% confidence interval [CI], −11.4 to 11.4, to 0 kg/m2; 95% CI, −8.5 to 8.5 for baseline BMI, and mean error, 0 kg/m2; 95% CI, −5.3 to 5.3 for BMI surveillance).
Conclusions:
The authors concluded that cardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood.
Perspective:
This study reports that although PRS was statistically significantly associated with BMI in young adulthood and midlife, the association was fairly modest with insufficient precision for clinically relevant prediction of midlife BMI. In fact, traditional clinical BMI assessment in young adulthood (age range, 18-30 years) offered more precision for prediction of an individual’s BMI 25 years later in midlife, with measurement of BMI serially offering the most precise predictions. Furthermore, fitness, activity, and self-reported parental history of overweight had a comparable association with BMI in midlife as the PRS, suggesting that higher levels of fitness and activity may limit obesity independent of polygenic risk. Contemporary obesity prevention efforts should focus on phenotypic characteristics (most prominently young adulthood BMI) and early fitness and physical activity.
Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Prevention, Sports and Exercise Cardiology, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Exercise, Sports and Exercise and Congenital Heart Disease and Pediatric Cardiology
Keywords: Body Mass Index, Exercise, Metabolic Syndrome, Obesity, Overweight, Physical Fitness, Phenotype, Primary Prevention, Risk Assessment, Young Adult
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