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

Area of Science:

• Genetics and Public Health
• Epidemiology
• Metabolic Health

Background:

• Observational studies suggest physical inactivity and sedentary time link to weight gain, but reverse causality is possible.
• Determining the true causal direction between sedentary behavior, physical activity, and adiposity is challenging due to observational study limitations.

Purpose of the Study:

• To investigate the bidirectional causality between physical inactivity, sedentary time, and body mass index (BMI).
• To differentiate causal links from reverse causality and confounding factors in the relationship between sedentary behavior and adiposity.

Main Methods:

• Utilized bidirectional Mendelian randomization analysis with the CAUSE method.
• Employed genome-wide association study data for physical activity, sedentary time (n=91,105), and BMI (n=806,834).
• Applied multiple Mendelian randomization methods including inverse variance-weighted, MR-Egger, and weighted median, accounting for pleiotropy and sample overlap.

Main Results:

• Confirmed bidirectional causality between sedentary time and BMI; longer sedentary time increased BMI, and higher BMI led to more sedentary time.
• Demonstrated that higher moderate and vigorous physical activity causally reduce BMI.
• Found evidence suggesting the association between higher BMI and lower physical activity is likely due to horizontal pleiotropy, not direct causality.

Conclusions:

• The bidirectional causal link between sedentary time and BMI highlights the importance of reducing sedentary behavior for weight management.
• Interventions targeting adiposity may offer additional benefits by potentially decreasing sedentary time.
• Mendelian randomization provides robust evidence for causal relationships obscured by observational study limitations.