Exercise Prevents Depression

Original Investigation
January 23, 2019

Assessment of Bidirectional Relationships Between Physical Activity and Depression Among AdultsA 2-Sample Mendelian Randomization Study

JAMA Psychiatry. Published online January 23, 2019. doi:10.1001/jamapsychiatry.2018.4175
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Key PointsQuestion  Does physical activity have a potential causal role in reducing risk for depression?

Findings  In this 2-sample mendelian randomization study using genetic instruments from large-scale genome-wide association studies to support potential causal inference, higher levels of physical activity (indexed by objective accelerometer data) were linked to reduced odds for major depression.

Meaning  Findings strengthen empirical support for physical activity as an effective prevention strategy for depression.


Importance  Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.

Objective  To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.

Design, Setting, and Participants  This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes—self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)—and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR–Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.

Main Outcomes and Measures  MDD and physical activity.

Results  GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = −0.08 in mean acceleration per MDD vs control status; 95% CI, −0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, −0.008 to 0.05; P = .15).

Conclusions and Relevance  Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed—but not self-reported—physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.


Depression is a common psychiatric condition that represents a leading cause of disability worldwide.1 Despite this, efforts to prevent depression have been challenging, with few established protective factors, particularly modifiable targets for prevention. One promising target is physical activity, defined broadly as musculoskeletal movement resulting in energy expenditure.2 The relationship between physical activity and depression has received much attention in recent years. For example, meta-analytic data from randomized clinical trials3 have suggested that physical activity is linked to reduced depressive symptoms in at-risk populations, and prospective studies4,5 have demonstrated associations between higher levels of physical activity and decreased risk for later depression.

Although such findings point to a potential protective role of physical activity for depression, several questions remain. First, does physical activity causally influence risk for depression—or is this better explained by reverse causation? Some studies6,7 show that depression may also lead to reduced physical activity, but few studies have simultaneously tested both directional relationships. Second, does measurement of physical activity matter? Literature to date has relied mostly on self-reported measures of activity,5 which may be subject to confounding by participant mood, memory inaccuracy, and social desirability bias.8 Third, does the relationship between physical activity and depression persist when potential confounding is minimized? Although randomized clinical trials minimize confounding from unaccounted variables by design, they are intensive to conduct and have been of relatively limited size, with a mean of fewer than 60 participants per trial.3,9,10 More critically, randomized clinical trials have focused on treating symptoms in depressed individuals rather than testing preventive effects of physical activity on depression, which has population-wide implications but requires large samples unselected for depression. The most convincing evidence to date that physical activity is associated with a reduced risk for depression comes from meta-analyses of prospective studies,5which are high quality yet still limited by the breadth of behavioral, social, and genetic confounders that cannot be fully ruled out in observational designs.

Mendelian randomization (MR) is an alternative method for potential causal inference that treats genetic variation as a natural experiment in which individuals are essentially assigned to higher vs lower mean levels of a nongenetic exposure during their lifetime.11 Because genetic variants are considered to be allocated randomly before birth, they are relatively independent of environmental factors and established well before onset of disease, thereby minimizing issues of residual confounding and reverse causation that limit typical observational studies. If an exposure such as physical activity causally influences an outcome such as depression, then a variant that affects physical activity should be expected to influence depression to a proportional degree, provided no separate pathway exists by which this variant can affect depression, a phenomenon known as horizontal pleiotropy. Under these conditions, variants strongly associated with an exposure of interest may serve as proxies, or instruments, for estimating potential causal relationship with an outcome (Figure 1). In a 2-sample MR design, instruments can be extracted from summary statistics of large-scale, nonoverlapping genome-wide association studies (GWAS), which have recently become available for physical activity12 and major depressive disorder (MDD).13 Herein, we apply bidirectional MR to assess the potential causal relationship of physical activity with the risk for depression, and vice versa. Furthermore, we examine genetic instruments for physical activity assessed subjectively via self-report and objectively using wearable accelerometers.

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