Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses
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Editor’s Note on Methodological Criticism and an Updated Analysis Objective: To investigate the shape of the causal relation between body mass index (BMI) and mortality. Design: Linear and non-linear mendelian randomisation analyses. Setting: Nord-Trøndelag Health (HUNT) Study (Norway) and UK Biobank (United Kingdom). Participants: Middle to early late aged participants of European descent: 56 150 from the HUNT Study and 366 385 from UK Biobank. Main outcome measures: All cause and cause specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. Results: 12 015 and 10 344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0-29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (−1% to 27%) lower risk in low normal weight participants (BMI 18.5-19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22-25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers. Conclusions: The previously observed J shaped relation between BMI and risk of all cause mortality appears to have a causal basis, but subgroup analyses by smoking status revealed that the BMI-mortality relation is likely comprised of at least two distinct curves, rather than one J shaped relation. An increased risk of mortality for being underweight was only evident in ever smokers.
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With individual level data and a continuous exposure, non-linear Mendelian randomization can be applied to estimate whether the causal effect of the exposure on the outcome varies across different levels of the exposure.
“With individual level data and a continuous exposure, non-linear MR can be applied to estimate whether the causal effect of the exposure on the outcome varies across different levels of the exposure.30,108”
From Mendelian randomization (2022) · cites this paper as [108]
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Obesity is a chronic progressive relapsing disease of particular interest for internal medicine
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Genetically Predicted Body Mass Index and Mortality in Chronic Obstructive Pulmonary Disease
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Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study
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- Authors
- Sun, Y.-Q., Burgess, S., Staley, J. R., Wood, A. M., Bell, S., Kaptoge, S. K., Guo, Q., Bolton, T. R., Mason, A. M., Butterworth, A. S., Di Angelantonio, E., Vie, G. Å., Bjørngaard, J. H., Kinge, J. M., Chen, Y., & Mai, X.-M.
- Affiliations
- Norwegian University of Science and Technology (NO)
- University of Cambridge (GB)
- Norwegian Institute of Public Health (NO)
- University of Ottawa (CA)
- Corresponding author
- Burgess, Stephen
- ORCID
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2019-03-26
- Volume
- 364
- Pages
- l1042
- ISSN
- 1756-1833 (ISSN-L)
- PMC
- PMC6434515
- OpenAlex
- W2916194715
- Cited by
- 193
- References
- 36
- Citations by year
- 2026: 6 · 2025: 22 · 2024: 29 · 2023: 26 · 2022: 48 · 2021: 36 · 2020: 22 · 2019: 4
- FWCI
- 16.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- BMJ (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
- HighWire Press Open Archive (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (204623/Z/16/Z, 204623)
- National Institute for Health and Care Research (NF-SI-0617-10113)
- British Heart Foundation (RG/18/13/33946, CH/12/2/29428, RG/13/13/30194)
- Department of Health and Social Care
- Norges Forskningsråd
- Medical Research Council (MR/L003120/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Keywords
- body mass index, all-cause mortality, obesity paradox, underweight, J-shaped relationship, smoking status, cardiovascular mortality, cancer mortality, HUNT study, UK Biobank, middle-aged and older adults
- MeSH terms
- Adult, Aged, Cardiovascular Diseases, Cause of Death, Female, United Kingdom, Humans, Male, Middle Aged, Neoplasms, Norway, Obesity, Risk Factors, Thinness, Body Mass Index, Sex Distribution, Mendelian Randomization Analysis
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