Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.Author summary: Decline in daily physical activity is thought to be a key contributor to the global obesity epidemic. However, the impact of sedentariness on adiposity may be in part determined by a person’s genetic constitution. The specific genetic variants that are sensitive to physical activity and regulate adiposity remain largely unknown. Here, we aimed to identify genetic variants whose effects on adiposity are modified by physical activity by examining ~2.5 million genetic variants in up to 200,452 individuals. We also tested whether adjusting for physical activity as a covariate could lead to the identification of novel adiposity variants. We find robust evidence of interaction with physical activity for the strongest known obesity risk-locus in the FTO gene, of which the body mass index-increasing effect is attenuated by ~30% in physically active individuals compared to inactive individuals. Our analyses indicate that other similar gene-physical activity interactions may exist, but better measurement of physical activity, larger sample sizes, and/or improved analytical methods will be required to identify them. Adjusting for physical activity, we identify 11 novel adiposity variants, suggesting that accounting for physical activity or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.