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

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.