Can the impact of childhood adiposity on disease risk be reversed? A Mendelian randomization study.
Open accessPreprint — published as 10.1136/bmj.m1203 · Paper page
Abstract
Objective: To evaluate whether early life adiposity has an independent effect on later life disease risk or whether its influence is mediated by adulthood body mass index (BMI). Design: Two-sample univariable and multivariable Mendelian randomization. Setting: The UK Biobank (UKB) prospective cohort study and four large-scale genome-wide association study (GWAS) consortia. Participants: 453,169 participants enrolled in the UKB and a combined total of over 700,000 individuals from different GWAS consortia. Exposures: Measured BMI during adulthood (mean age: 56.5) and self-reported adiposity at age 10. Main outcome measures: Coronary artery disease (CAD), type 2 diabetes (T2D), breast cancer and prostate cancer. Results: Individuals with genetically predicted higher BMI in early life had increased odds of CAD (OR:1.49, 95% CI:1.33-1.68) and T2D (OR:2.32, 95% CI:1.76-3.05) based on univariable MR (UVMR) analyses. However, there was little evidence of a direct effect (i.e. not via adult BMI) based on multivariable MR (MVMR) estimates (CAD OR:1.02, 95% CI:0.86-1.22, T2D OR:1.16, 95% CI:0.74-1.82). In the MVMR analysis of breast cancer risk, there was strong evidence of a protective direct effect for early BMI (OR:0.59, 95% CI:0.50-0.71), although adult BMI did not appear to have a direct effect on this outcome (OR:1.08, 95% CI:0.93-1.27). Adding age of menarche as an additional exposure provided weak evidence of a total causal effect (UVMR OR:0.98, 95% CI:0.91-1.06) but strong evidence of a direct causal effect, independent of early and adult BMI (MVMR OR:0.90, 95% CI:0.85-0.95). Weak evidence of a causal effect was observed in the MVMR analysis of prostate cancer (early life BMI OR:1.06, 95% CI:0.81-1.40, adult BMI OR:0.87, 95% CI:0.70-1.08). Conclusions: Our findings suggest that increased CAD and T2D risk attributed to early life adiposity can be mitigated if individuals reduce their weight in later life. However, having a low BMI during childhood may increase risk of breast cancer regardless of changes to weight in later life, with timing of puberty also putatively playing an important role.
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It is possible to separate the effects of body mass index in childhood and adulthood on a variety of health outcomes using different instruments for the two exposure periods.
“For example, it is possible to separate the effects of body mass index in childhood and adulthood on a variety of health outcomes using different instruments for the two exposure periods.111”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [111]
NLRP3 inflammasome (upstream of IL1b) is under exploration as a potential therapeutic target.
“Nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome (upstream of IL1b) is under exploration as a potential therapeutic target 102 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [102]
If there are many variants in an analysis, leaving one variant out at a time is unlikely to change the estimate substantially, and leaving out subsets of the variants may be more appropriate.
“If there are many variants in an analysis, leaving one variant out at a time is unlikely to change the estimate substantially, and leaving out subsets of the variants (say, a randomly chosen 30% at a time 101 ) may be more appropriate.”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [101]
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Ooi, B. N. S., Loh, H. W., Ho, P. J., Milne, R. L., Giles, G. G., Gao, C., Kraft, P., John, E. M., Swerdlow, A. J., Brenner, H., et al. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz124 · Cited by 64 · see citing works
Risk Factors for Breast Cancer at Young Ages in Twins: An International Population-Based Study
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High body mass index and cancer risk—a Mendelian randomisation study
Benn, M., Tybjærg‐Hansen, A., Smith, G. D., & Nordestgaard, B. G. (2016) · European Journal of Epidemiology · doi:10.1007/s10654-016-0147-5 · Cited by 59 · see citing works
Bonilla, C., Lewis, S. J., Martin, R. M., Donovan, J., Hamdy, F. C., Neal, D. E., Eeles, R. A., Easton, D. F., Kote‐Jarai, Z., Olama, A. A. A., et al. (2016) · BMC Medicine · doi:10.1186/s12916-016-0602-x · Cited by 46 · see citing works
Change in Overweight from Childhood to Early Adulthood and Risk of Type 2 Diabetes
Cadwell, J. B., & Shukla, A. P. (2018) · New England Journal of Medicine · doi:10.1056/nejmc1805984 · Cited by 34 · see citing works
Harrison, S., Tilling, K. M., Turner, E. L., et al. (2016) · Cancer Causes & Control · doi:10.1007/s10552-016-0827-1 · Cited by 23 · see citing works
Self-citationCommentary: Mendelian randomization with multiple exposures: the importance of thinking about time
Labrecque, J. A., & Swanson, S. A. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz234 · Cited by 20 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [79]Hughes RA Davies NM Davey Smith G Selection bias in instrumental variable analyses. bioRxiv [Preprint] 2018:192237. 10.1101/192237%J. · DOI
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Sanderson, E., Glymour, M. M., Holmes, M. V., Kang, H., Morrison, J., Munafò, M. R., Palmer, T., Schooling, C. M., Wallace, C., Zhao, Q., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-021-00092-5 · Cited by 2,229 · see citing works
Self-citationSkrivankova, V. W., Richmond, R. C., Woolf, B. A. R., Davies, N. M., Swanson, S. A., VanderWeele, T. J., Timpson, N. J., Higgins, J. P. T., Dimou, N., Langenberg, C., et al. (2021) · BMJ · doi:10.1136/bmj.n2233 · Cited by 1,648 · see citing works
Guidelines for performing Mendelian randomization investigations
Burgess, S., Davey Smith, G., Davies, N. M., Dudbridge, F., Gill, D., Glymour, M. M., Hartwig, F. P., Holmes, M. V., Minelli, C., Relton, C. L., et al. (2020) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15555.2 · Cited by 1,273 · see citing works
Mendelian randomisation for mediation analysis: current methods and challenges for implementation
Carter, A. R., Sanderson, E., Hammerton, G., Richmond, R. C., Davey Smith, G., Heron, J., Taylor, A. E., Davies, N. M., & Howe, L. D. (2021) · European Journal of Epidemiology · doi:10.1007/s10654-021-00757-1 · Cited by 1,215 · see citing works
Self-citationMendelian Randomization: Concepts and Scope
Richmond, R. C., & Davey Smith, G. (2022) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a040501 · Cited by 841 · see citing works
Self-citationDavey Smith, G., Holmes, M. V., Davies, N. M., & Ebrahim, S. (2020) · European Journal of Epidemiology · doi:10.1007/s10654-020-00622-7 · Cited by 287 · see citing works
Holmes, M. V., Richardson, T. G., Ference, B. A., Davies, N. M., & Davey Smith, G. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00493-1 · Cited by 184 · see citing works
Self-citationFang, S., Yarmolinsky, J., Gill, D., Bull, C. J., Perks, C. M., the PRACTICAL Consortium, Davey Smith, G., Gaunt, T. R., & Richardson, T. G. (2023) · PLOS Medicine · doi:10.1371/journal.pmed.1003988 · Cited by 55 · see citing works
Self-citationInterpretation of mendelian randomization using one measure of an exposure that varies over time
Morris, T. T., Heron, J., Sanderson, E., Smith, G. D., & Tilling, K. (2021) · doi:10.1101/2021.11.18.21266515 · Cited by 58 · see citing works
Self-citationHowe, L. J., Tudball, M., Davey Smith, G., & Davies, N. M. (2022) · International Journal of Epidemiology · doi:10.1093/ije/dyab208 · Cited by 48 · see citing works
Self-citationDeng, Y.-T., Li, Y.-Z., Huang, S.-Y., Ou, Y.-N., Zhang, W., Chen, S.-D., Zhang, Y.-R., Yang, L., Dong, Q., Feng, J.-F., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01604-9 · Cited by 45 · see citing works
Martin, S., Tyrrell, J., Thomas, E. L., Bown, M. J., Wood, A. R., Beaumont, R. N., Tsoi, L. C., Stuart, P. E., Elder, J. T., Law, P., et al. (2022) · eLife · doi:10.7554/elife.72452 · Cited by 43 · see citing works
- Authors
- Richardson, T. G., Sanderson, E., Elsworth, B., Tilling, K., & Davey Smith, G.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Richardson, Tom G.
- Venue
- BMJ
- Publisher
- openRxiv
- Published
- 2019-10-05
- Volume
- 369
- Pages
- m1203-m1203
- ISSN
- 1756-1833 (ISSN-L)
- PMC
- PMC7201936
- OpenAlex
- W3011942165
- Cited by
- 321
- References
- 89
- Citations by year
- 2026: 32 · 2025: 51 · 2024: 65 · 2023: 55 · 2022: 62 · 2021: 40 · 2020: 14 · 2019: 1
- FWCI
- 25.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- BMJ (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Wellcome Trust (102215/2/13/2), 217065/Z/19/Z, 102215)
- University Hospitals Bristol NHS Foundation Trust
- UK Research and Innovation (MR/S003886/1)
- National Institute for Health and Care Research (MC_UU_00011/1)
- University of Bristol (MC_UU_00011/1, 102215/2/13/2, MC_UU_00,011/3, MC_UU_00011/2)
- Medical Research Council (102215, MC_UU_00011/2, MC_UU_00011/3, MR/S003886/1, 102215/2/13/2, MC_PC_17228, MC_PC_15018, MC_UU_00011/1, MC_PC_19009, MC_UU_00011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Keywords
- body size, body mass index, body size perception, coronary artery disease, type 2 diabetes, breast cancer, prostate cancer, age at menarche, causal mediation analysis, adult body size, disease risk, genetic variants, Mendelian randomization, UK Biobank
- MeSH terms
- Breast Neoplasms, Child, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, United Kingdom, Humans, Male, Middle Aged, Obesity, Prospective Studies, Prostatic Neoplasms, Risk Factors, Genetic Variation, Body Mass Index, Risk Assessment, Adiposity, Genome-Wide Association Study, Mendelian Randomization Analysis
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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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