Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analysesBMJ 2019; 364 doi: https://doi.org/10.1136/bmj.l1042 (Published 26 March 2019) Cite this as: BMJ 2019;364:l1042
- Yi-Qian Sun, researcher1,
- Stephen Burgess, statistician2 3,
- James R Staley, postdoctoral researcher3 4,
- Angela M Wood, senior lecturer3 5,
- Steven Bell, genetic epidemiologist3 5,
- Stephen K Kaptoge, lecturer3 5,
- Qi Guo, postdoctoral researcher3 5,
- Thomas R Bolton, data manager3 5,
- Amy M Mason, research associate3,
- Adam S Butterworth, reader3 5,
- Emanuele Di Angelantonio, professor3 5,
- Gunnhild Å Vie, postdoctoral researcher6,
- Johan H Bjørngaard, professor6,
- Jonas Minet Kinge, researcher7 8,
- Yue Chen, professor9,
- Xiao-Mei Mai, professor6
- 1Department of Clinical and Molecular Medicine (IKOM), NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- 2MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge CB2 0SR, UK
- 3Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- 4MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- 5NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- 6Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- 7Norwegian Institute of Public Health, Oslo, Norway
- 8University of Oslo, Oslo, Norway
- 9School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Correspondence to: S Burgess
- Accepted 12 February 2019
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.
Contributors: YQS, SBu, and XMM contributed to the research questions and study design. XMM contributed to data collection for HUNT Study. YQS, SBu, and JRS conducted statistical analyses. YQS, SBu, and XMM interpreted the results and wrote the initial draft of the manuscript. JRS, SBe, AMW, SKK, QG, TRB, AMM, ASB, EDA, GÅV, JHB, JMK, and YC interpreted the data and helped to write the final draft of the manuscript. SB, YQS, and XMM had full access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. SBu and YQS are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. YQS and SBu contributed equally to this work.
Funding: YQS and this work were supported by the Norwegian Cancer Society (project ID 5769155-2015) and Research Council of Norway “Gaveforsterkning”. GÅV and JMK were supported by the Research Council of Norway (grant No 250335). SBu is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant No 204623/Z/16/Z). This work was supported by core funding from the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), and National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: The HUNT Study has ethical approval from The Regional Committee for Medical Research in Norway (REK). Approval for individual projects is regulated in conjunction with The Norwegian Social Science Data Services (NSD). The UK Biobank study has ethical approval from the North West Multi-centre Research Ethics Committee (MREC). Approval for individual projects is covered by the Research Tissue Bank (RTB).
Data sharing: Data from the HUNT Study and UK Biobank are available on application.
Transparency: The manuscripts guarantors (SBu and YQS) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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