TY - JOUR
T1 - Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity
AU - Carrasquilla, Germán D
AU - García-Ureña, Mario
AU - Fall, Tove
AU - Sørensen, Thorkild IA
AU - Kilpeläinen, Tuomas
N1 - © 2022, Carrasquilla et al.
PY - 2022
Y1 - 2022
N2 - 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 used 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 = 3.8 × 10-4), 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.
AB - 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 used 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 = 3.8 × 10-4), 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.
U2 - 10.7554/eLife.70386
DO - 10.7554/eLife.70386
M3 - Journal article
C2 - 35254260
VL - 11
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e70386
ER -