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Multicenter Study
. 2019 Mar 26:364:l1042.
doi: 10.1136/bmj.l1042.

Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Yi-Qian Sun  1 , Stephen Burgess  2   3 , James R Staley  3   4 , Angela M Wood  3   5 , Steven Bell  3   5 , Stephen K Kaptoge  3   5 , Qi Guo  3   5 , Thomas R Bolton  3   5 , Amy M Mason  3 , Adam S Butterworth  3   5 , Emanuele Di Angelantonio  3   5 , Gunnhild Å Vie  6 , Johan H Bjørngaard  6 , Jonas Minet Kinge  7   8 , Yue Chen  9 , Xiao-Mei Mai  6
Affiliations
Multicenter Study

Body mass index and all cause mortality in HUNT and UK Biobank studies: linear and non-linear mendelian randomisation analyses

Yi-Qian Sun et al. BMJ. .

Abstract

Editor's note: Please see the Editor's Note (doi: https://doi.org/10.1136/bmj.l1042) 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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Conflict of interest statement

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.

Figures

Fig 1
Fig 1
Description of method for estimating shape of body mass index-mortality relation by using genetic variants
Fig 2
Fig 2
Non-linear mendelian randomisation. Dose-response curve between body mass index and all cause mortality for HUNT Study and UK Biobank. Gradient at each point of the curve is the localised average causal effect. Shaded areas represent 95% confidence intervals
Fig 3
Fig 3
Non-linear mendelian randomisation. Dose-response curve between body mass index and all cause mortality in men and women for HUNT Study and UK Biobank. Gradient at each point of the curve is the localised average causal effect. Shaded areas represent 95% confidence intervals
Fig 4
Fig 4
Non-linear mendelian randomisation. Dose-response curve between body mass index and all cause mortality in never smokers and ever smokers for HUNT Study and UK Biobank. Gradient at each point of the curve is the localised average causal effect. Shaded areas represent 95% confidence intervals
Fig 5
Fig 5
Non-linear mendelian randomisation in UK Biobank. Dose-response curve between body mass index and cause specific mortality. Gradient at each point of the curve is the localised average causal effect. Shaded areas represent 95% confidence intervals
See this image and copyright information in PMC

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