Cited by 762Physical Activity and HealthGenetic Associations and EpidemiologyGenetics and Physical Performance

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

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Choi, Karmel W., Chen, Chia-Yen, Stein, Murray B., Klimentidis, Yann C., Wang, Min-Jung, Koenen, Karestan C., Smoller, Jordan W., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium·2019·JAMA Psychiatry

DOI 10.1001/jamapsychiatry.2018.4175PMC PMC6450288

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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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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: Choi, Karmel W.
Chen, Chia-Yen
Stein, Murray B.
Klimentidis, Yann C.
Wang, Min-Jung
Koenen, Karestan C.
Smoller, Jordan W.
Venue: JAMA Psychiatry
Publisher: American Medical Association (AMA)
Published: 2019-04-01
Volume: 76
Issue: 4
Pages: 399
ISSN: 2168-622X (ISSN-L)
DOI: 10.1001/jamapsychiatry.2018.4175
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
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 › Public Health, Environmental and Occupational Health › 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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Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults: A 2-Sample Mendelian Randomization Study

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