Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Abstract

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Genetic Pathways Underlying Individual Differences in Regular Physical Activity

“…Table 3 summarizes the current evidence from the eight published GWAS on PA (63)(64)(65)(66)(67)(68)(69)(70).…”

“…Table 3 gives a selection of the main genes prioritized by the GWAS studies on PA, with the clear disclaimer that a much richer set can be extracted from the (supplements to the) the original reports ( 63 , 65 , 66 , 68 , 70 ). A list of genes that appear in more than one study stand out for further scrutiny in future replication studies, which include CADM2 , KANSL1 , SYT4 , and AKAP10 .…”

“…Interestingly, the latter ACTN3 gene immediately demonstrates that associations between PA ability and PA behavior at the single variant level can be misleading. Extensive links to exercise ability have been shown for a common ACTN3 variant that introduces a premature stop codon (rs1815739, R577X), but neither this variant nor nearby variants in LD with it were associated with PA phenotypes in the meta-analysis of Wang et al ( 70 ). Instead, the genome-wide significant association between ACTN3 and MVPA found was due to a previously unidentified missense variant (rs2229456) that was shown to lower maximal force production during contraction, thus providing protection from exercise-induced muscle damage.…”

“…For VEB, a dichotomy of participant spending no versus at least 2 d of sports or other exercises for 15+ min added another five genome-wide significant loci, with the most strongly associated variant in the CADM2 gene showing up in MVPA as well. In a large trans-ancestry GWAS meta-analysis on sedentary behaviors and MVPA, combining results in up to 703,901 participants from 51 studies, Wang et al ( 70 ) further increased the yield for MVPA, even with a relatively “poor” PA phenotype. For a dichotomy of not engaging versus regularly engaging in 20 min·wk −1 of MVPA, lead SNPs from 11 loci were genome-wide significant (six not reported before), and four of these had significant reverse effects on sedentary behaviors.…”

“…Five studies computed h 2 SNP for PA traits, three of which used self-reported PA ( 66 , 70 ) and three used device-based PA ( 65 , 66 , 68 ). SNP-based heritability proved to be systematically higher in the studies using accelerometers than in the self-report studies.…”