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Can the impact of childhood adiposity on disease risk be reversed? A Mendelian randomization study

By Tom G Richardson, Eleanor Sanderson, Benjamin Elsworth, Kate Tilling, George Davey Smith

Posted 05 Oct 2019
medRxiv DOI: 10.1101/19008011

ObjectiveTo evaluate whether early life adiposity has an independent effect on later life disease risk or whether its influence is mediated by adulthood body mass index (BMI). DesignTwo-sample univariable and multivariable Mendelian randomization. SettingThe UK Biobank (UKB) prospective cohort study and four large-scale genome-wide association study (GWAS) consortia. Participants453,169 participants enrolled in the UKB and a combined total of over 700,000 individuals from different GWAS consortia. ExposuresMeasured BMI during adulthood (mean age: 56.5) and self-reported adiposity at age 10. Main outcome measuresCoronary artery disease (CAD), type 2 diabetes (T2D), breast cancer and prostate cancer. ResultsIndividuals with genetically predicted higher BMI in early life had increased odds of CAD (OR:1.49, 95% CI:1.33-1.68) and T2D (OR:2.32, 95% CI:1.76-3.05) based on univariable MR (UVMR) analyses. However, there was little evidence of a direct effect (i.e. not via adult BMI) based on multivariable MR (MVMR) estimates (CAD OR:1.02, 95% CI:0.86-1.22, T2D OR:1.16, 95% CI:0.74-1.82). In the MVMR analysis of breast cancer risk, there was strong evidence of a protective direct effect for early BMI (OR:0.59, 95% CI:0.50-0.71), although adult BMI did not appear to have a direct effect on this outcome (OR:1.08, 95% CI:0.93-1.27). Adding age of menarche as an additional exposure provided weak evidence of a total causal effect (UVMR OR:0.98, 95% CI:0.91-1.06) but strong evidence of a direct causal effect, independent of early and adult BMI (MVMR OR:0.90, 95% CI:0.85-0.95). Weak evidence of a causal effect was observed in the MVMR analysis of prostate cancer (early life BMI OR:1.06, 95% CI:0.81-1.40, adult BMI OR:0.87, 95% CI:0.70-1.08). ConclusionsOur findings suggest that increased CAD and T2D risk attributed to early life adiposity can be mitigated if individuals reduce their weight in later life. However, having a low BMI during childhood may increase risk of breast cancer regardless of changes to weight in later life, with timing of puberty also putatively playing an important role.

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