Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity

Abstract

Physical inactivity and increased sedentary time are associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity and increased sedentary time. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirectional causality between physical inactivity, sedentary time and adiposity by bidirectional Mendelian randomization analysis. We assessed genetic liability using results from genome-wide association studies for accelerometer-based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance-weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide significant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causal for higher BMI [beta (95%CI) from CAUSE method: 0.11 (0.02, 0.2), P=0.02], and higher BMI was causal for longer sedentary time (0.13 (0.08, 0.17), P=6.3.x10-4). Our analyses suggest that higher moderate and vigorous physical activity are causal for lower BMI (moderate: -0.18 (-0.3,-0.05), P=0.006; vigorous: -0.16 (-0.24,-0.08), P=3.8x10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to horizontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting adiposity may lead to additional health benefits by reducing sedentary time.

Environment-wide and epigenome-wide association study of adiposity in “Children of 1997” birth cohort

“…MR studies do not suggest that coffee consumption affects adiposity (38, 56), so the observed association might be due to confounding or chance. Similarly, the associations of chocolate and sweets intake with lower BMI at ~17.6 years, as well as physical activity with higher BMI at ~17.6 years are not consistent with RCTs of dark chocolate consumption (35) and physical activity (37)), or MR studies of physical activity (41), and might be due to confounding or reverse causality.…”

“…Regarding the comparison with RCTs and MR studies, we found RCTs on dark chocolate consumption (35), water consumption promotion (36), and physical activity (37), and MR studies related to drinking coffee (38), dairy intake (39), binge eating (40), physical activity (41), snoring (42), puberty (43, 44), birth weight (45), and maternal adiposity (46, 47) (Table 10). The available evidence from both RCTs and MR studies show that more physical activity lowers BMI (37), and MR studies show that dairy intake (39), binge eating (40), and earlier puberty (43, 44) are associated with higher BMI.…”

“…Nevertheless, one MR study suggested higher dairy intake was associated with higher adult's BMI. 41 Coffee consumption NA Genetically predicted more coffee intake was not associated with obesity, BMI, or waist circumference in two large adult population cohorts. 40 Also, most MR studies do not support a role of caffeine consumption on BMI or waist circumstance.…”

Physical Activity and Its Association With Body Mass Index: A Cross-Sectional Analysis in Middle-Aged Adults From 4 Sub-Saharan African Countries

“…These may include PA intensity, where PA performed at a higher intensity may be associated with lower BMI. 43 Conversely, higher BMI may be contributing to lower PA as observed in a Mendelian randomization study by Carrasquilla et al, 22 where higher MVPA was causal for lower BMI and at the same time higher BMI was causal for less PA. In addition, Kroesen and De Vos 23 found lower PA as a consequence of higher BMI.…”

“…16,17 Nevertheless, evidence is fairly consistent on the association of higher PA with lower BMI. [18][19][20][21] However, though PA is known to be associated with lower BMI, the reverse may also be true as bidirectional causal relationships between PA and BMI have been observed in a Mendelian randomization study 22 and higher BMI has been seen to result in less transportrelated PA. 23 Nevertheless, there remains, a lack of evidence on the impact of domain-specific PA on BMI, particularly on the African continent as patterns of PA in work, leisure, and transport-related PA domains differ across regions of the world. 8 Therefore, we aimed to describe and compare PA domains between middle-aged men and women from East, West, and South African countries and evaluate the association between time spent in these PA domains with BMI.…”