Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomization study

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Objective: To evaluate whether early life body size has an independent effect on later life disease risk or whether its influence is mediated by adulthood body size.

Design: Two-sample univariable and multivariable Mendelian randomization.

Setting: The UK Biobank (UKB) prospective cohort study and four large-scale genome-wide association study (GWAS) consortia.

Participants: 453,169 participants enrolled in the UKB and a combined total of over 700,000 individuals from different GWAS consortia.

Exposures: Measured body mass index during adulthood (mean age: 56.5) and self-reported perceived body size at age 10.

Main outcome measures: Coronary artery disease (CAD), type 2 diabetes (T2D), breast cancer and prostate cancer.

Results: Individuals with a larger genetically predicted body size in early life had increased odds of CAD (OR:1.49 per change in body size category unless stated otherwise, 95% CI:1.33 to 1.68) and T2D (OR :2.32, 95% CI:1.76 to 3.05) based on univariable MR (UVMR) analyses. However, there was little evidence of a direct effect (i.e. not via adult body size) based on multivariable MR (MVMR) estimates (CAD OR:1.02, 95% CI:0.86 to 1.22, T2D OR:1.16, 95% CI:0.74 to 1.82). In the MVMR analysis of breast cancer risk, there was strong evidence of a protective direct effect for larger body size in early life (OR:0.59, 95% CI:0.50 to 0.71), with less evidence of a direct effect of adult body size on this outcome (OR:1.08, 95% CI:0.93 to 1.27). Adding age of menarche as an additional exposure provided weak evidence of a total causal effect (UVMR OR:0.98, 95% CI:0.91 to 1.06) but strong evidence of a direct causal effect, independent of early life and adult body size (MVMR OR:0.90, 95% CI:0.85 to 0.95). There was no strong evidence of a causal effect of either early or later life measures on prostate cancer (early life body size OR:1.06, 95% CI:0.81 to 1.40, adult body size OR:0.87, 95% CI:0.70 to 1.08).

Conclusions: Our findings suggest that the positive association between childhood body size and CAD and T2D risk can be attributed to individuals remaining large into later life. However, having a smaller body size during childhood may increase risk of breast cancer regardless of body size in adulthood, with timing of puberty also putatively playing an important role.
Original languageEnglish
Article number2020;369:m1203
Number of pages12
Issue number8244
Publication statusPublished - 6 May 2020


  • Mendelian randomization
  • Early life adiposity
  • Mediation
  • UK Biobank


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