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.

Uncontrolled eating: a unifying heritable trait linked with obesity, overeating, personality and the brain

“…Such environment-mediated associations provide support for causal associations between traits (Turkheimer & Harden, 2014). Furthermore, external environmental factors influence the heritability of traits: for instance the heritability of BMI is lower in people that exercise (McCaffery et al, 2009;Horn et al, 2015;Graff et al, 2017). Therefore, heritability only stands for genetic potential for a trait to manifest, and this potential can be altered with interventions.…”

The Combination of Physical Activity and Sedentary Behaviors Modifies the Genetic Predisposition to Obesity

“…All previous studies have investigated the interaction between genetic risk of obesity and PA (13)(14)(15)(16)(17)(18)(19) or sedentary behaviors (16,20,21) as separate exposures. However, there has been new evidence suggesting that both PA and sedentary behaviors are independently associated with detrimental health outcomes, and that they act in an additive manner on health outcomes (22).…”

“…To our knowledge, there have been very few studies that have investigated genotype-lifestyle interaction effects on BMI, with most studies focusing on the effect of individual genes (7)(8)(9)(10)(11)(12). Only a few studies have investigated whether polygenic risk scores or genetic profile risk scores for BMI (GPRS-BMI), which provide greater BMI prediction than a single gene, interact with physical activity (PA) (13)(14)(15)(16)(17)(18)(19) or sedentary behaviors (16,20,21). To date, only one study has investigated the modifying effect of combined PA and TV viewing on the genetic predisposition related to adiposity outcomes (15).…”

Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions

“…The genetic marginal effect estimates, calculated separately within each of the two strata, were compared using a heterogeneity test [12] to infer the presence or absence of SNP × smoking interaction effects. The same analyses were performed using physical activity as a binary stratifying variable in up to 180,287 European-ancestry adults (42,065 physically active vs. 138,222 physically inactive) [24]. We calculated Spearman correlations between the P -values derived from the marginal effects meta-analysis and the P int from the interaction effects meta-analysis (i.e., the between-strata heterogeneity test for SNP × smoking and SNP × physical activity interactions from the GIANT consortium); these tests were undertaken for all SNPs and those SNPs that were nominally significant ( P m <0.05) in the marginal effects analysis.…”