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

Abstract

ABSTRACTObjectivesTo estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomization framework.DesignMendelian randomization analyses of two prospective population-based cohorts.SettingIndividuals of European ancestries living in Norway or the United Kingdom.Participants56,150 participants from the Trøndelag Health Study (HUNT) in Norway and 366,385 participants from UK Biobank recruited by postal invitation.OutcomesAll-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer).ResultsA previously published non-linear Mendelian randomization 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 re-analysis of these data using the more reliable doubly-ranked stratification method still indicated a J-shaped relationship, but with 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 non-cardiovascular non-cancer mortality above 26 kg/m2, and for cancer mortality above 30 kg/m2. In UK Biobank, the association between genetically-predicted BMI and mortality at high BMI levels was stronger in women than in men.ConclusionThis research challenges findings from previous conventional observational epidemiology and Mendelian randomization investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m2. Our results provide evidence that reductions in BMI will only increase mortality risk for a small proportion of the population, and increases in BMI will increase mortality risk for those with BMI above 25 kg/m2.Strengths and limitations of the studyMendelian randomization design minimizes bias due to confounding and reverse causationLarge sample sizes enable powerful analyses even in low BMI individualsValidity of the genetic variants as instrumental variables cannot be verifiedBias due to selection could be non-negligible and could vary across strataAll estimates are averaged across a stratum of the population; individual effects of raising or lowering BMI may vary between individuals