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

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

Mendelian randomisation analyses of two prospective population-based cohorts.

Individuals of European ancestries living in Norway or the UK.

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

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

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.

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.