Body mass index and all-cause mortality in HUNT and UK biobank studies: revised non-linear Mendelian randomisation analyses

Abstract

Objectives: To estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework.

Design: Mendelian randomisation analyses of two prospective population-based cohorts.

Setting: Individuals of European ancestries living in Norway or the UK.

Participants: 56 150 participants from the Trøndelag Health Study (HUNT) in Norway and 366 385 participants from UK Biobank recruited by postal invitation.

Outcomes: All-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer).

Results: A previously published non-linear Mendelian randomisation analysis of these data using the residual stratification method suggested a J-shaped association between genetically predicted BMI and mortality outcomes with the lowest mortality risk at a BMI of around 25 kg/m². However, the 'constant genetic effect' assumption required by this method is violated. The reanalysis of these data using the more reliable doubly-ranked stratification method provided some indication of a J-shaped relationship, but with much less certainty as there was less precision in estimates at the lower end of the BMI distribution. Evidence for a harmful effect of reducing BMI at low BMI levels was only present in some analyses, and where present, only below 20 kg/m². A harmful effect of increasing BMI for all-cause mortality was evident above 25 kg/m², for cardiovascular mortality above 24 kg/m², for cancer mortality above 30 kg/m² and for non-cardiovascular non-cancer mortality above 26 kg/m². In UK Biobank, the association between genetically predicted BMI and mortality at high BMI levels was stronger in women than in men.

Conclusion: This research challenges findings from previous conventional observational epidemiology and Mendelian randomisation investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m². Our results provide some evidence that reductions in BMI will increase mortality risk for a small proportion of the population, and clear evidence that increases in BMI will increase mortality risk for those with BMI above 25 kg/m².

Keywords: EPIDEMIOLOGY; GENETICS; Obesity; Observational Study.