Polygenic Risk, Fitness, and Obesity in the Coronary Artery Risk Development in Young Adults (CARDIA) Study

This cohort study quantifies the relative importance of a polygenic risk score, fitness, activity, parental history of overweight, and body mass index in young adulthood regarding body mass index trends over 25 years. Key PointsQuestionWhat is the added value of polygenic risk in predicting body mass index (BMI) over time beyond young adulthood BMI, parental history of overweight, fitness, and activity? FindingsAmong 1608 white individuals and 909 black individuals in this cohort study of young adults in the United States, polygenic risk scores did not offer accurate prediction of BMI in midlife, whereas BMI in young adulthood (in their 20s) offered a more accurate prediction of long-term BMI trends. MeaningComprehensive clinical risk profiles (incorporating BMI, its change over time, and behavioral factors), but not polygenic risk scores, offer substantial predictive ability for future BMI in the context of obesity prevention. ImportanceObesity is a major determinant of disease burden worldwide. Polygenic risk scores (PRSs) have been posited as key predictors of obesity. How a PRS can be translated to the clinical encounter (especially in the context of fitness, activity, and parental history of overweight) remains unclear. ObjectiveTo quantify the relative importance of a PRS, fitness, activity, parental history of overweight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in young adulthood on BMI trends over 25 years. Design, Setting, and ParticipantsThis population-based prospective cohort study at 4 US centers 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. Main Outcomes and MeasuresBody mass index at the initial visit and 25 years later. ResultsThis study evaluated an obesity PRS from a recently reported study of 1608 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/m(2) [95% CI, -11.4 to 11.4] to 0 kg/m(2) [95% CI, -8.5 to 8.5] for baseline BMI and mean error 0 kg/m(2) [95% CI, -5.3 to 5.3] for BMI surveillance). Conclusions and RelevanceCardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood. Fitness has a comparable association with future BMI as does the PRS. Caution should be exercised in the widespread use of polygenic risk for obesity prevention in adults, and close clinical surveillance and fitness may have prime roles in limiting the adverse consequences of elevated BMI on health.