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

Abstract

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.

Fig 1. Power to identify PA-adjusted main, joint or GxPA interaction effects in 200,000 individuals (45,000 inactive, 155,000 active).

The plots compare power to identify genome-wide significant main effects (P_adjPA<5x10^-8, dashed black), joint effects (P_JOINT<5x10^-8, dotted green) or GxPA interaction effects (P_INT<5x10^-8, solid magenta) as well as the power to identify Bonferroni-corrected interaction effects (P_INT<0.05/number of loci, solid orange) for the SNPs that reached a genome-wide significant PA-adjusted main effect association (P_adjPA<5x10^-8). The power computations were based on analytical power formulae provided elsewhere [50] and were conducted a-priori based on various types of known realistic BMI effect sizes [51]. Panels A, C, E: Assuming an effect in inactive individuals similar to a small ($R_{INACT}^2=0.01\%$, comparable to the known BMI effect of the NUDT3 locus), medium ($R_{INACT}^2=0.07\%$, comparable to the known BMI effect of the BDNF locus) and large ($R_{INACT}^2=0.34\%$, comparable to the known BMI effect of the FTO locus) realistic effect on BMI and for various effects in physically active individuals (varied on the x axis); Panels B,D,F: Assuming an effect in physically active individuals similar to the small, medium and large realistic effects of the NUDT3, BDNF and FTO loci on BMI and for various effects in inactive individuals (varied on x axis).