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

Objective: To investigate the shape of the causal relationship between body mass index (BMI) and mortality. Design: Linear and non-linear Mendelian randomization analyses of two prospective population-based cohorts. Setting: Middle-aged to early late-aged individuals of European descent. Participants: 56,150 participants from the Nord-Trøndelag Health Study (HUNT) in Norway and 366,385 participants from UK Biobank recruited by postal invitation. Main outcome measures: All-cause and cause-specific (cardiovascular, cancer, and non-cardiovascular non-cancer) mortality. Results: In total 12,015 and 10,344 participants died during a median of 18.5 and 7.0 years’ follow-up in the HUNT and UK Biobank studies respectively. Linear Mendelian randomization analyses indicated an overall positive association between genetically-predicted BMI and all-cause mortality risk. A 1 kg/m2 increase in genetically-predicted BMI led to a 5% (95% confidence interval [CI]: 1%, 8%) higher mortality risk in overweight individuals (BMI 25.0-29.9), and a 9% (95% CI: 4%, 14%) higher mortality risk in obese individuals (BMI ≥ 30.0), but 34% (95% CI: 16%, 48%), lower risk in underweight (BMI < 18.5) and 14% (95% CI: -1%, 27%) lower risk in low normal weight individuals (BMI 18.5-19.9). Non-linear Mendelian randomization indicated a J-shaped relationship between genetically-predicted BMI and all-cause mortality risk, with the nadir of risk at BMI about 22-25 kg/m2 for the overall sample. Increased risk of all-cause mortality in overweight and obese individuals was more evident in women. However, subgroup analyses by smoking status suggested a monotone increasing relationship of BMI with mortality in never-smokers, but a non-monotone relationship in ever-smokers. Conclusion: The previously observed J-shaped relationship between BMI and mortality appears to have a causal basis, but subgroup analyses by smoking status revealed the BMI—mortality relationship is likely comprised of at least two distinct curves, rather than a single J-shaped relationship. Increased mortality risk for being underweight was only evident in ever-smokers.
YQS and this work were supported by The Norwegian Cancer Society (project ID 5769155-2015) and The Research Council of Norway “Gaveforsterkning”. GÅV and JMK were supported by The Research Council of Norway (grant number 250335). S Burgess is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). 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