Comparison of intergenerational instrumental variable analyses of body mass index and mortality in UK Biobank

Ciarrah Jane Barry, David Carslake, Kaitlin H. Wade, Eleanor Sanderson, George Davey Smith

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BACKGROUND: An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants. 

METHODS: In Cox regression models, parental BMI was instrumented by offspring BMI using an 'offspring as instrument' (OAI) estimation and by offspring BMI-related genetic variants in a 'proxy-genotype Mendelian randomization' (PGMR) estimation. 

RESULTS: Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent-offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother-son) and 1.23 (95% CI: 1.16, 1.29; father-daughter). 

CONCLUSION: Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them.

Original languageEnglish
Pages (from-to)545-561
Number of pages17
JournalInternational Journal of Epidemiology
Issue number2
Early online date19 Apr 2023
Publication statusPublished - 30 Apr 2023
Externally publishedYes

Bibliographical note

All the authors work in a unit funded by the UK Medical Research Council (MC_UU_00011/1) and by the University of Bristol. At the beginning of this project, K.H.W. was funded by a Wellcome Trust Investigator award (202802/Z/16/Z; PI: Professor Nicholas Timpson) and was then supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust (218495/Z/19/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Data availability:
UK Biobank data are available upon application as described at


  • body mass index
  • instrumental variable
  • intergenerational
  • Mendelian randomization
  • mortality
  • offspring as instrument
  • proxy genotype
  • UK Biobank

ASJC Scopus subject areas

  • Epidemiology


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