Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants identifies multiple variants including CADM2 and APOE
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Abstract
Background/objectives Physical activity (PA) protects against a wide range of diseases. Habitual PA appears to be heritable, motivating the search for specific genetic variants that may inform efforts to promote PA and target the best type of PA for each individual.Subjects/methods We used data from the UK Biobank to perform the largest genome-wide association study of PA to date, using three measures based on self-report (n max = 377,234) and two measures based on wrist-worn accelerometry data (n max = 91,084). We examined genetic correlations of PA with other traits and diseases, as well as tissue-specific gene expression patterns. With data from the Atherosclerosis Risk in Communities (ARIC; n = 8,556) study, we performed a meta-analysis of our top hits for moderate-to-vigorous PA (MVPA).Results We identified ten loci across all PA measures that were significant in both a basic and a fully adjusted model (p < 5 × 10-9). Upon meta-analysis of the nine top hits for MVPA with results from ARIC, eight were genome-wide significant. Interestingly, among these, the rs429358 variant in the APOE gene was the most strongly associated with MVPA, whereby the allele associated with higher Alzheimer's risk was associated with greater MVPA. However, we were not able to rule out possible selection bias underlying this result. Variants in CADM2, a gene previously implicated in obesity, risk-taking behavior and other traits, were found to be associated with habitual PA. We also identified three loci consistently associated (p < 5 × 10-5) with PA across both self-report and accelerometry, including CADM2. We found genetic correlations of PA with educational attainment, chronotype, psychiatric traits, and obesity-related traits. Tissue enrichment analyses implicate the brain and pituitary gland as locations where PA-associated loci may exert their actions.Conclusions These results provide new insight into the genetic basis of habitual PA, and the genetic links connecting PA with other traits and diseases.
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Recent GWAS studies have indicated a genetic contribution to physical activity, finding three variants associated with standard UK Biobank activity metrics.
“Recent GWAS studies have indicated a genetic contribution to physical activity, finding three variants8 associated with standard UK Biobank activity metrics9.”
From GWAS identifies 14 loci for device-measured physical activity and sleep duration (2018) · cites this paper as [8]
We found concordance for loci previously reported using UK Biobank data for overall and moderate intensity activity, sleep duration, and sedentary time.
“We found concordance for loci previously reported using UK Biobank data for overall (near PML) and moderate intensity activity8 (near LINC02210-CRHR1, and SYT4), sleep duration12,19,23,24 (near PUM1, CHCHD5, SAMMSON, BTBD9-AS1, LRP12, EBLN3P, BSX, KCNH5, PRKCB, and RPGRIP1L), and sedentary time (near LINC01930 and LY6H) (Supplementary Data 3).”
From GWAS identifies 14 loci for device-measured physical activity and sleep duration (2018) · cites this paper as [8]
Previous self-reported literature has significantly underestimated heritability for physical activity (~5% vs ~20% for accelerometer-measured traits).
“For example, we found that previous self-reported literature has significantly underestimated heritability for physical activity8 (~ 5% vs. ~ 20% for accelerometer-measured traits).”
From GWAS identifies 14 loci for device-measured physical activity and sleep duration (2018) · cites this paper as [8]
The larger-sample sizes currently available for self-reported phenotypes result in more identified loci, however heritability and potential explained variance appears higher for the objective traits.
“The larger-sample sizes that are currently available for self-reported phenotypes results in more identified loci8, however, heritability and potential explained variance appears higher for the objective traits.”
From GWAS identifies 14 loci for device-measured physical activity and sleep duration (2018) · cites this paper as [8]
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- Authors
- Klimentidis, Y. C., Raichlen, D. A., Bea, J., Garcia, D. O., Wineinger, N. E., Mandarino, L. J., Alexander, G. E., Chen, Z., & Going, S. B.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Klimentidis, Yann C.
- ORCID
- Venue
- International Journal of Obesity
- Published
- 2018-06
- Volume
- 42
- Issue
- 6
- Pages
- 1161-1176
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- PMC
- PMC6195860
- OpenAlex
- W2807749226
- Cited by
- 403
- References
- 84
- Citations by year
- 2026: 25 · 2025: 44 · 2024: 96 · 2023: 65 · 2022: 60 · 2021: 43 · 2020: 37 · 2019: 28 · 2018: 5
- FWCI
- 17.29
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UA Campus Repository (The University of Arizona) (acceptedVersion)
- Funders
- Arizona Department of Health Services
- Medical Research Council (MC_PC_17228)
- National Institute on Aging (P30AG019610)
- National Human Genome Research Institute (U01HG004402)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK095032)
- National Institute of Environmental Health Sciences (P30ES006694)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Physiology › Physical Activity and Health
- Keywords
- physical activity behavior, genetic variants, CADM2, apolipoprotein E, moderate-to-vigorous physical activity, genetic correlation, tissue-specific gene expression, accelerometry, self-reported physical activity, educational attainment, chronotype, psychiatric traits, obesity-related traits, Alzheimer's disease risk, brain, pituitary gland
- MeSH terms
- Adult, Aged, Apolipoproteins E, Female, United Kingdom, Humans, Male, Middle Aged, Phenotype, Genetic Variation, Exercise, Cell Adhesion Molecules, Biological Specimen Banks, Genetic Predisposition to Disease, Genome-Wide Association Study
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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