Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study
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Abstract
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.
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Physical exercise for approximately 45 minutes per day can significantly reduce the risk of MDD.
“Furthermore, physical exercise for approximately 45 minutes per day can significantly reduce the risk of MDD. 320 , 321”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [320]
The Results report significantly lower MDD risk per 1-SD increase in accelerometer-measured physical activity. The Discussion says this increase has no straightforward conversion to exercise duration; its examples are 15 minutes of vigorous activity or just over an hour of moderate activity, not approximately 45 minutes per day. The finding concerns physical activity broadly, rather than exercise alone. (LLM, conf=0.89)
Experimental — accuracy not yet measuredRecent large-scale observational and Mendelian randomisation studies suggest that higher levels of physical activity can confer protection against mental disorders.
“There are recent large-scale observational [18] and Mendelian randomisation studies [124] suggesting that higher levels of PA can confer protection against mental disorders.”
From Exercise as Medicine for Mental and Substance Use Disorders: A Meta-review of the Benefits for Neuropsychiatric and Cognitive Outcomes (2020) · cites this paper as [124]
The Abstract reports a large-scale Mendelian randomization analysis suggesting that objectively measured physical activity protects against major depressive disorder. The claim broadens that finding to mental disorders generally; the paper studied depression, and it found no significant protective relationship for self-reported activity. The separate observational-study citation is not assessed here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInitial analyses found no clear evidence that either self-reported moderate-vigorous physical activity or objectively measured physical activity causally influenced risk of major depression.
“Initial analyses found no clear evidence that either form of activity causally influenced risk of major depression.”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [33]
Using a relaxed p value threshold of p<1x10-7 that identified 10 SNPs, there was strong evidence for objectively measured overall physical activity as a protective factor for major depression: IVW OR=0.74, 95% CI: 0.59-0.92, p=0.006.
“Using this genetic instrument, there was strong evidence for objectively measured overall physical activity as a protective factor for major depression: IVW (inverse-variance weighted) OR=0.74, 95% CI: 0.59-0.92, p=0.006.”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [33]
The estimate for objectively measured physical activity and major depression was consistent across multiple sensitivity analyses to test for pleiotropy.
“This was consistent across multiple sensitivity analyses to test for pleiotropy.”
From A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders (2020) · cites this paper as [33]
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- Authors
- Choi, K. W., Chen, C.-Y., Stein, M. B., Klimentidis, Y. C., Wang, M.-J., Koenen, K. C., Smoller, J. W., & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
- Affiliations
- Broad Institute (US)
- University of California San Diego (US)
- University of Arizona (US)
- Harvard University (US)
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2019-04-01
- Volume
- 76
- Issue
- 4
- Pages
- 399
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6450288
- OpenAlex
- W2913696992
- Semantic Scholar
- 85716820b9138618988cf8f830e7af1b2131d426
- Cited by
- 744
- References
- 34
- Citations by year
- 2026: 54 · 2025: 105 · 2024: 204 · 2023: 120 · 2022: 87 · 2021: 84 · 2020: 53 · 2019: 35 · 2018: 2
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- ResearchOnline at James Cook University (James Cook University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- IRIS (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- VU Research Portal (submittedVersion, other-oa)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Amgen
- Pfizer
- Brigham and Women's Hospital
- Massachusetts General Hospital
- University of Southern California
- Kaiser Permanente
- Massachusetts Institute of Technology
- Emory University
- F. Hoffmann-La Roche
- Aarhus Universitet
- Aarhus Universitetshospital
- Johns Hopkins University
- Universität Basel
- Virginia Commonwealth University
- Wellcome Trust
- QIMR Berghofer Medical Research Institute
- Broad Institute
- Universitätsmedizin Göttingen
- National Institute for Health and Care Research
- King's College London
- University College London
- University of Oxford
- Newcastle University
- University of Glasgow
- Cardiff University
- Trinity College Dublin
- Universiteit Leiden
- Rijksuniversiteit Groningen
- James Cook University
- Queensland University of Technology
- University of Queensland
- Vrije Universiteit Amsterdam
- Albert-Ludwigs-Universität Freiburg
- Gentofte Hospital
- Dalhousie University
- GGZ inGeest
- Lundbeckfonden
- University of Toronto
- Università degli Studi di Trento
- Karolinska Institutet
- Westfälische Wilhelms-Universität Münster
- Leids Universitair Medisch Centrum
- Universitair Medisch Centrum Groningen
- Rigshospitalet
- Region Hovedstaden
- Háskóli Íslands
- Universidad de Granada
- Tartu Ülikool
- Rheinische Friedrich-Wilhelms-Universität Bonn
- H. Lundbeck A/S
- Centre for Cognitive Ageing and Cognitive Epidemiology
- National Institutes of Health
- School of Medicine, Emory University
- University of North Carolina at Chapel Hill
- University of California, San Diego
- McDonnell Center for Systems Neuroscience
- Stanley Center for Psychiatric Research, Broad Institute
- Department of Psychiatry, Columbia University
- Department of Psychiatry, University of Toronto
- Medical Research Council (MR/K026992/1, MC_UU_00007/10)
- Biotechnology and Biological Sciences Research Council (BB/F019394/1)
- Queensland Brain Institute
- Institute of Molecular and Cell Biology
- Statens Serum Institut
- Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
- National Institute of Mental Health (T32MH017119, U01MH109536, K24MH094614)
- National Cancer Institute
- Janssen Research and Development
- Institute of Genetics
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- NHLBI Division of Intramural Research
- Topics
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- physical activity, depression, major depressive disorder, bidirectional relationship, causal inference, accelerometer-measured activity, self-reported physical activity, moderate-to-vigorous physical activity, genetic instruments, depression prevention, adults, European ancestry, horizontal pleiotropy, UK Biobank, Psychiatric Genomics Consortium, MR-PRESSO
- MeSH terms
- Adult, Depressive Disorder, Major, Major Depressive Disorder, Humans, Exercise, Case-Control Studies, Genome-Wide Association Study, Mendelian Randomization Analysis, Self Report, Accelerometry, Protective Factors
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