1. Epidemiology and Global Health
  2. Genetics and Genomics

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

  1. Germán D Carrasquilla  Is a corresponding author
  2. Mario García-Ureña
  3. Tove Fall
  4. Thorkild IA Sørensen
  5. Tuomas O Kilpeläinen
  1. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
  2. Molecular Epidemiology, Department of Medical Sciences, and Science for Life Laboratory, Uppsala University, Sweden
  3. Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
https://doi.org/10.7554/eLife.70386
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Cite this article
  1. Germán D Carrasquilla
  2. Mario García-Ureña
  3. Tove Fall
  4. Thorkild IA Sørensen
  5. Tuomas O Kilpeläinen
(2022)
Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity
eLife 11:e70386.
https://doi.org/10.7554/eLife.70386
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5 figures, 9 tables and 1 additional file

Figures

Figure 1
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Mendelian randomization assumptions and directional associations between physical activity, sedentary time and adiposity.

Panel A shows Mendelian randomization assumptions when estimating the causal association between a given exposure and outcome: (1) The instruments are associated with the exposure, (2) the instruments do not cause the outcome independently from the exposure (horizontal uncorrelated pleiotropy), and (3) the effects of the exposure on the outcome are not influenced by any confounders (horizontal correlated pleiotropy). Panel B indicates a unidirectional causal effect of physical activity or sedentary time on adiposity, whereas panel C indicates a unidirectional causal effect of adiposity on physical activity or sedentary time. Panel D indicates a bidirectional causal relationship where physical activity or sedentary time has a causal effect on adiposity, but at the same time, adiposity has a causal effect on physical activity or sedentary time. Figure icons were created with BioRender.com.

Figure 2
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Causal estimates for Mendelian randomization analyses using the CAUSE, inverse-variance-weighted (IVW), weighted median, and weighted mode methods.

Median causal estimates for Mendelian randomization analyses using the CAUSE method are shown in the left panel and mean causal estimates from the inverse variance weighted (IVW), weighted median (Wmedian) and weighted mode (Wmode) methods are shown in the right panel after outlier removal and accounting for horizontal pleiotropy. A diamond (♢) in the estimate for CAUSE indicates that the sharing model fit the data better than the causal model, that is that the association between the traits was more likely to be explained by horizontal correlated pleiotropy than causality. PA, physical activity; BMI, body mass index. Figure icons were created with BioRender.com.

Appendix 1—figure 1
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Scatter plot for CAUSE test statistics on the causal association between BMI and sedentary time.

Effect estimates for body mass index (x-axis) are plotted against estimates for sedentary time (y-axis). Error bars indicate 95% confidence intervals and the dotted line indicates the median causal effect of BMI on sedentary time.

Appendix 1—figure 2
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Estimates from the CAUSE method for the causal relationship between physical activity or sedentary time and waist-hip ratio, waist circumference, or body fat percentage.

Median causal estimates for Mendelian randomization analyses using the CAUSE method. A diamond (♢) in the estimate for CAUSE indicates that the sharing model fit the data better than the causal model, that is that the association between the traits was more likely to be explained by horizontal correlated pleiotropy than causality. PA, physical activity; WHRadjBMI, waist-to-hip ratio adjusted for body mass index; WCadjBMI, waist circumference adjusted for body mass index; BFP, body fat percentage. Figure icons were created with BioRender.com.

Appendix 1—figure 3
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Leave-one-out forest and funnel sensitivity plots after outlier extraction.

Tables

Table 1
Results for Mendelian randomization analyses using the CAUSE method.
Causal model better fit for the data
DirectionMedian causal effect (95% CI)Median q (CI)P causal vs sharing
Vigorous PA→ BMI–0.16 (-0.24,–0.08)0.19 (0, 0.86)3.8 × 10–04
Moderate PA→ BMI–0.18 (-0.3,–0.05)0.20 (0.01, 0.86)0.006
Sedentary time → BMI0.11 (0.02, 0.20)0.19 (0, 0.86)0.02
BMI → Sedentary time0.13 (0.08, 0.17)0.18 (0, 0.85)6.3 × 10–4
Sharing model better fit for the data
DirectionMedian shared effect (CI)Median q (CI)P causal vs sharing
BMI → Vigorous PA–0.16 (-0.19,–0.14)0.90 (0.77, 0.98)0.35
BMI → Moderate PA–0.14 (-0.19,–0.11)0.77 (0.55, 0.95)0.31

  1. BMI, Body mass index (BMI); SE, standard error; N SNPs, number of single-nucleotide polymorphism; P, P-value; PA, physical activity; IVW, inverse variance weighted; CI, 95% confidence interval.

  2. The results display the data according to the goodness-of-fit for the causal or the sharing model. The median q value indicates the proportion of variants with correlated pleiotropy.

Table 2
Mendelian randomization results for inverse variance weighted, weighted median, weighted mode, and MR-Egger methods.
DirectionVigorous physical activity → BMIModerate physical activity → BMISedentary time → BMI
MR methodbetaSEp-valueN SNPsbetaSEp-valueN SNPsbetaSEp-valueN SNPs
IVW–0.170.080.045–0.240.120.0530.110.080.165
Weighted median–0.180.100.085–0.180.120.1330.100.100.295
Weighted mode–0.190.120.195–0.140.150.4330.080.140.595
MR-Egger1.332.210.5950.120.450.8430.490.360.265
DirectionBMI → Vigorous physical activityBMI → Moderate physical activityBMI → Sedentary time
IVW–0.070.020.0157–0.060.030.03550.070.030.0157
Weighted mode–0.010.060.83570.020.060.6855–0.060.080.4657
Weighted median–0.040.030.27570.0030.040.93550.030.040.4857
MR-Egger0.130.070.06570.160.070.0455–0.020.080.7657
BMI, Body mass index (BMI); SE, standard error; N SNPs, number of single nucleotide polymorphism; IVW, inverse variance weighted; CI, 95% confidence interval.

  1. The results display the data according to the goodness-of-fit for the causal or the sharing model. The median q value indicates the proportion of variants with correlated pleiotropy. CI, confidence interval; PA, physical activity; BMI, body mass index; P, P-value.

Appendix 1—table 1
CAUSE expected log pointwise posterior density (ELPD) results for each combination of traits.
Vigorous physical activity → BMIBMI → vigorous physical activity
Model 1Model 2Delta_ELPDSE_delta_ELPDzDelta_ELPDSE_delta_ELPDZ
NullSharing–17.474.24–4.12–251.8821.54–11.69
NullCausal–18.984.68–4.05–252.2221.65–11.65
SharingCausal–1.510.45–3.36–0.350.90–0.38
Moderate physical activity → BMIBMI → Moderate physical activity
NullSharing–8.502.86–2.97–119.3915.15–7.88
NullCausal–9.833.39–2.90–119.7715.34–7.81
SharingCausal–1.340.53–2.52–0.380.77–0.49
Sedentary time → BMIBMI → Sedentary time
NullSharing–6.512.57–2.53–137.84157.46–8.75
NullCausal–7.673.14–2.44–138.8915.88–8.75
SharingCausal–1.160.57–2.05–1.060.33–3.22

  1. BMI, Body mass index; SE, standard error; NA, not applicable; CI, 95% confidence interval.

Appendix 1—table 2
CAUSE posterior probabilities and q values for the causal effect and the shared effect.
ModelCausal effect (CI)Shared effect (CI)q (CI)Sharing vs causal model p-value
Vigorous physical activity → BMI
SharingNA–0.18 (-0.25,–0.12)0.85 (0.57, 0.98)3.80E-04
Causal–0.16 (-0.24,–0.08)0 (-0.31, 0.31)0.19 (0.00, 0.86)
Moderate physical activity → BMI
SharingNA–0.2 (-0.33,–0.11)0.75 (0.35, 0.96)5.80E-03
Causal–0.18 (-0.3,–0.05)–0.01 (-0.44, 0.39)0.2 (0.01, 0.86)
Sedentary time → BMI
SharingNA0.13 (0.06, 0.23)0.69 (0.25, 0.95)2.00E-02
Causal0.11 (0.02, 0.20)0 (-0.32, 0.32)0.19 (0, 0.86)
BMI → Vigorous physical activity
SharingNA–0.16 (-0.19,–0.14)0.9 (0.77, 0.98)0.35
Causal–0.15 (-0.2,–0.08)0.01 (-0.18, 0.21)0.21 (0.01, 0.83)
BMI → Moderate physical activity
SharingNA–0.14 (-0.19,–0.11)0.77 (0.55, 0.95)0.31
Causal–0.11 (-0.19,–0.03)0 (-0.28, 0.2)0.23 (0.01, 0.84)
BMI → Sedentary time
SharingNA0.14 (0.12, 0.17)0.9 (0.73, 0.98)6.30E-04
Causal0.13 (0.08, 0.17)0 (-0.23, 0.26)0.18 (0.00, 0.85)

  1. BMI, Body mass index; NA, not applicable; CI, 95% confidence interval.

Appendix 1—table 3
Approximation of the causal estimates in absolute units.
Original causal estimates (weighted median)Conversion of causal estimatesConverted causal estimates
AnalysisN SNPsBetaSEpEquationSDexposureSDoutcome 
Vigorous physical activity → BMI1,036–0·09 SD0·006 SD9.28E-57(Beta*SDoutcome)/
SDexposure /
(0,01*24 hours)		NA4·807 kg/m2–0·48 kg/m2 per hour of moderate physical activity per day
Moderate physical activity → BMI914–0·05 SD0·005 SD1.21E-20(Beta*SDoutcome)/
SDexposure /
(0,01*24 hours)		3.76%4·807 kg/m2–0·27 kg/m2 per hour of moderate physical activity per day
Sedentary time → BMI1,0360·06 SD0·005 SD6.33E-30(Beta*SDoutcome)/
SDexposure /
(0,01*24 hours)		7.38%4·807 kg/m20,14 kg/m2 per hour of sedentary time per day
BMI → Sedentary time11,8490·16 SD0·009 SD2.87E-68(Beta*SDoutcome)/
SDexposure *(0·01*24 hours)		4·807 kg/m27.38%3·54 min of sedentary time per kg/m2 per day
Original units of the traits:Moderate physical activity: Probability of moderate physical activity in a 30s-epoch frame (Doherty et al., 2018)
Sedentary time: Probability of sedentary time in a 30s-epoch frame (Doherty et al., 2018)
BMI: kg/m2 (Pulit et al., 2019)
Note: For vigorous physical activity, SD exposure could not be found, thus we use the same as for moderate physical activity, i.e. 3·76%

  1. SNP, single nucleotide polymorphism; BMI, SE, standard error; SD, standard deviation; Body mass index (BMI).

Appendix 1—table 4
Mendelian randomization results using the IVW, Egger, weighted median and weighted mode methods of for the causal effect of moderate or vigorous physical activity or sedentary time on BMI.
 Before outlier extraction
 Vigorous physical activity → BMIModerate physical activity → BMISedentary time → BMI
MR methodSNPbetaSEp-valueSNPbetaSEp-valueSNPbetaSEp-value
Egger51.332.210.5930.120.450.8480.460.640.50
Weighted median5–0.180.100.083–0.180.120.1380.020.090.82
IVW5–0.170.080.043–0.240.120.0580.040.110.72
Weighted mode5–0.190.120.193–0.140.150.438–0.050.180.78
Sensitivity testEstimatep-value/CIEstimatep-value/CIEstimatep-value/CI
Q (p-value)1.650.83.60.1723.081.70E-03
I2 (CI)0.00%(0,0%; 49,5%)44.30%(0,0%; 83,4%)69.70%(36,8%; 85,4%)
Q-Q' (p-value)0.460.51.750.191.960.16
Egger intercept (p-value)–0.040.29–0.010.19–0.010.75
Rucker TestIVWIVWIVW
 After outlier extraction
 Vigorous physical activity → BMIModerate physical activity → BMISedentary time → BMI
MR methodSNPbetaSEp-valueSNPbetaSEp-valueSNPbetaSEp-value
EggerNANANANANANANANA50.490.360.26
Weighted medianNANANANANANANANA50.100.100.29
IVWNANANANANANANANA50.110.080.16
Weighted modeNANANANANANANANA50.080.140.59
Sensitivity testEstimatep-value/CIEstimatep-value/CIEstimatep-value/CI
Q (p-value)NANANANA4.70.32
I2 (CI)NANANANA15(0·0%; 82·3%)
Q-Q' (p-value)NANANANA1.410.24
Egger intercept (p-value)NANANANA–1.00E-020.24
Rucker TestNANAIVW

  1. BMI, Body mass index (BMI); MR, Mendelian randomization; SNP, single nucleotide polymorphism; SE, standard error; NA, not applicable; IVW, inverse variance weighted; CI, 95% confidence interval. NA: not applicable. Note: No outlier extraction was performed for moderate physical activity → BMI and vigorous physical activity → BMI directions, since Q test and I2 did not indicate heterogeneity.

Appendix 1—table 5
Mendelian randomization results using the IVW, Egger, weighted median and weighted mode methods of BMI on moderate PA, vigorous PA, or sedentary time.
Before outlier extraction
 BMI → Vigorous physical activityBMI → Moderate physical activityBMI → Sedentary time
MR methodSNPbetaSEp-valueSNPbetaSEp-valueSNPbetaSEp-value
Egger640.090.080.22650.170.080.0465–0.100.090.28
Weighted median64–0.040.030.21650.0040.040.92650.030.040.44
IVW64–0.080.030.00565–0.050.030.09650.070.030.02
Weighted mode64–0.010.070.86650.020.050.7265–0.050.100.59
Sensitivity testEstimatep-value/CIEstimatep-value/CIEstimatep-value/CI
Q (p-value)92.49.30E-0383.730.0597.54.40E-03
I2 (CI)31.80%6·9%; 50·00%23.60%(0·00%; 44·20%)34.40%10·80%; 51·70%
Q-Q' (p-value)8.363.80E-0310.869.81E-046.591.00E-02
Egger intercept (p-value)–4.99E-039.90E-01–6.40E-039.81E-044.96E-032.00E-02
Rucker testEggerEggerEgger
After outlier extraction
 BMI → Vigorous physical activityBMI → Moderate physical activityBMI → Sedentary time
MR methodSNPbetaSEp-valueSNPbetaSEp-valueSNPbetaSEp-value
Egger570.130.070.06550.160.070.0457–0.020.080.76
Weighted median57–0.040.030.27552.95E-030.040.93570.030.040.48
IVW57–0.070.020.0155–0.060.030.03570.070.030.01
Weighted mode57–0.010.060.83550.020.060.6857–0.060.080.46
Sensitivity testEstimatep-value/CIEstimatep-value/CIEstimatep-value/CI
Q (p-value)61.880.2740.510.9156.290.46
I2 (CI)9.50%0·00%–35·10%0.00%(0·0%; 8·9%)0.50%0·0%; 31·50%
Q-Q' (p-value)9.791.75E-039.61.94E-031.622.00E-01
Egger intercept–5.70E-031.75E-03–6.44E-039.15E-052.60E-032.00E-01
Rucker testIVWIVWIVW

  1. BMI, Body mass index; MR, Mendelian randomization; SNP, single nucleotide polymorphism; SE, standard error; NA, not applicable; IVW, inverse variance weighted; CI, 95% confidence interval.

Appendix 1—table 6
CAUSE expected log pointwise posterior density (ELPD) results for central adiposity and fat percentage.
Vigorous physical activity → BFPBFP → vigorous physical activity
Model 1Model 2Delta_ELPDSE_delta_ELPDzDelta_ELPDSE_delta_ELPDz
NullSharing–23.554.67–5.04–360.4824.46–14.74
NullCausal–25.115.00–5.02–361.7724.49–14.77
SharingCausal–1.560.33–4.68–1.300.17–7.77
  Moderate physical activity → BFPBFP → Moderate physical activity
NullSharing–8.712.60–3.34–170.4617.46–9.76
NullCausal–10.113.13–3.23–171.5017.63–9.73
SharingCausal–1.400.53–2.65–1.030.54–1.90
  Sedentary time → BFPBFP → Sedentary time
NullSharing–9.743.30–2.95–143.0415.86–9.02
NullCausal–11.013.83–2.87–144.2516.13–8.94
SharingCausal–1.270.54–2.38–1.210.36–3.41
  
  Vigorous physical activity → WCadjBMIWCadjBMI → Vigorous physical activity
  Delta_ELPDSE_delta_ELPDzDelta_ELPDSE_delta_ELPDz
NullSharing0.570.077.71–6.373.13–2.03
NullCausal1.360.159.28–7.163.65–1.96
SharingCausal0.790.0710.60–0.790.54–1.46
  Moderate physical activity → WCadjBMIWCadjBMI → Moderate physical activity
NullSharing0.500.560.89–4.832.96–1.63
NullCausal1.010.871.16–5.403.58–1.51
SharingCausal0.510.361.44–0.560.65–0.87
  Sedentary time → WCadjBMIWCadjBMI → Sedentary time
NullSharing0.550.077.56–7.593.34–2.27
NullCausal1.390.168.55–8.613.97–2.17
SharingCausal0.830.099.21–1.020.65–1.56
Vigorous physical activity → WHRadjBMIWHRadjBMI → Vigorous physical activity
Delta_ELPDSE_delta_ELPDzDelta_ELPDSE_delta_ELPDz
NullSharing–0.911.19–0.770.060.840.07
NullCausal–1.682.10–0.800.311.520.21
SharingCausal–0.770.91–0.850.260.680.37
  Moderate physical activity → WHRadjBMIWHRadjBMI → Moderate physical activity
NullSharing0.480.163.000.220.770.28
NullCausal0.920.561.630.441.440.30
SharingCausal0.440.411.090.220.670.32
  Sedentary time → WHRadjBMIWHRadjBMI → Sedentary time
NullSharing0.570.115.29–6.723.44–1.95
NullCausal1.370.284.83–7.314.03–1.81
SharingCausal0.800.184.48–0.590.61–0.97

  1. BFP, body fat percentage; WCadjBMI, waist cirumference adjusted for body mass index; WHRadjBMI, waist-to-hip ratio adjusted for body mass index, SE, standard error; NA, not applicable; CI, 95% confidence interval.

Appendix 1—table 7
CAUSE posterior probabilities and q values for the causal and sharing models for central adiposity and body fat percentage.
ModelCausal Effect (CI)Shared effect (CI)Q (CI)Sharing vs causal model p-value
 Vigorous physical activity → BFP
SharingNA–0.18 (-0.23,–0.13)0.89 (0.67, 0.98)1.4e-06
Causal–0.17 (-0.24,–0.09)0 (-0.28, 0.26)0.19 (0, 0.86)
 Moderate physical activity → BFP
SharingNA–0.17 (-0.26,–0.09)0.78 (0.39, 0.97)0.0041
Causal–0.15 (-0.24,–0.05)0 (-0.32, 0.31)0.2 (0, 0.86)
 Sedentary time → BFP
SharingNA0.11 (0.06, 0.17)0.75 (0.37, 0.96)0.0088
Causal0.09 (0.03, 0.15)0 (-0.26, 0.27)0.19 (0, 0.86)
 BFP → Vigorous physical activity
SharingNA–0.27 (-0.29,–0.25)0.97 (0.92, 1)3.9e-15
Causal–0.26 (-0.31,–0.22)0 (-0.26, 0.22)0.18 (0, 0.85)
 BFP → Moderate physical activity
SharingNA–0.21 (-0.25,–0.18)0.91 (0.77, 0.99)0.029
Causal–0.19 (-0.26,–0.12)0 (-0.3, 0.31)0.19 (0, 0.86)
 BFP → Sedentary time
SharingNA0.2 (0.17, 0.24)0.91 (0.76, 0.99)0.00032
Causal0.19 (0.12, 0.25)0 (-0.33, 0.31)0.18 (0, 0.86)
 
 Vigorous physical activity → WCadjBMI
SharingNA–0.01 (-0.62, 0.59)0.12 (0, 0.72)1
Causal0 (-0.15, 0.14)0 (-0.55, 0.52)0.2 (0.01, 0.86)
 Moderate physical activity → WCadjBMI
SharingNA–0.14 (-0.98, 0.6)0.13 (0.01, 0.69)9.20E-01
Causal–0.03 (-0.36, 0.27)–0.03 (-0.83, 0.7)0.26 (0.01, 0.84)
 Sedentary time → WCadjBMI
SharingNA0.01 (-0.44, 0.57)0.12 (0, 0.71)1
Causal0 (-0.13, 0.14)0.01 (-0.41, 0.52)0.21 (0.01, 0.85)
 WCadjBMI → Vigorous physical activity
SharingNA–0.1 (-0.21,–0.05)0.59 (0.19, 0.92)0.072
Causal–0.07 (-0.14, 0)0 (-0.31, 0.36)0.19 (0, 0.86)
 WCadjBMI → Moderate physical activity
SharingNA–0.11 (-0.27,–0.04)0.47 (0.11, 0.88)0.19
Causal–0.06 (-0.14, 0.03)0 (-0.34, 0.36)0.19 (0, 0.86)
 WCadjBMI → Sedentary time
SharingNA0.1 (0.05, 0.2)0.63 (0.23, 0.93)0.059
Causal0.07 (0.01, 0.14)0.01 (-0.3, 0.48)0.17 (0, 0.85)
 
 Vigorous physical activity → WHRadjBMI
SharingNA–0.1 (-0.39, 0.07)0.36 (0.01, 0.86)0.2
Causal–0.06 (-0.16, 0.04)0 (-0.37, 0.44)0.19 (0, 0.86)
 Moderate physical activity → WHRadjBMI
SharingNA–0.04 (-0.48, 0.39)0.15 (0, 0.76)8.60E-01
Causal–0.03 (-0.14, 0.09)0 (-0.41, 0.4)0.2 (0, 0.86)
 Sedentary time → WHRadjBMI
SharingNA0.01 (-0.26, 0.34)0.12 (0, 0.72)1
Causal0 (-0.06, 0.07)0 (-0.22, 0.28)0.2 (0, 0.86)
 WHRadjBMI → Vigorous physical activity
SharingNA–0.04 (-0.3, 0.12)0.16 (0, 0.76)0.65
Causal–0.01 (-0.06, 0.03)0 (-0.25, 0.21)0.18 (0, 0.85)
 WHRadjBMI → Moderate physical activity
SharingNA–0.04 (-0.31, 0.14)0.16 (0, 0.75)6.30E-01
Causal–0.01 (-0.06, 0.03)0 (-0.25, 0.22)0.18 (0, 0.85)
 WHRadjBMI → Sedentary time
SharingNA0.07 (0.03, 0.18)0.49 (0.13, 0.89)0.17
Causal0.04 (-0.01, 0.09)0 (-0.29, 0.4)0.17 (0, 0.83)

  1. BFP, Body Fat Percentage; WCadjBMI, waist circumference adjusted for BMI; WHRadjBMI,waist-to-hip ratio adjusted for BMI; NA, not applicable; CI, 95% confidence interval.

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  1. Germán D Carrasquilla
  2. Mario García-Ureña
  3. Tove Fall
  4. Thorkild IA Sørensen
  5. Tuomas O Kilpeläinen
(2022)
Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity
eLife 11:e70386.
https://doi.org/10.7554/eLife.70386