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

TLDR

The study investigates whether genetically predicted body size in early life independently influences the risk of coronary artery disease, type 2 diabetes, breast cancer, and prostate cancer later in life, or whether its effect is mediated through adult body size. Using two‑sample Mendelian randomisation with data from 453,169 UK Biobank participants and over 700,000 individuals from GWAS consortia, the authors compared genetically predicted adult BMI and recalled childhood body size to assess disease risk. Genetically larger childhood body size increased odds of coronary artery disease (OR 1.49) and type 2 diabetes (OR 2.32), but multivariable analyses showed no direct effect beyond adult size; it was protective for breast cancer (OR 0.59) and had no clear impact on prostate cancer.

Abstract

To evaluate whether body size in early life has an independent effect on risk of disease in later life or whether its influence is mediated by body size in adulthood.Two sample univariable and multivariable mendelian randomisation.The UK Biobank prospective cohort study and four large scale genome-wide association studies (GWAS) consortiums.453 169 participants enrolled in UK Biobank and a combined total of more than 700 000 people from different GWAS consortiums.Measured body mass index during adulthood (mean age 56.5) and self-reported perceived body size at age 10.Coronary artery disease, type 2 diabetes, breast cancer, and prostate cancer.Having a larger genetically predicted body size in early life was associated with an increased odds of coronary artery disease (odds ratio 1.49 for each change in body size category unless stated otherwise, 95% confidence interval 1.33 to 1.68) and type 2 diabetes (2.32, 1.76 to 3.05) based on univariable mendelian randomisation analyses. However, little evidence was found of a direct effect (ie, not through adult body size) based on multivariable mendelian randomisation estimates (coronary artery disease: 1.02, 0.86 to 1.22; type 2 diabetes:1.16, 0.74 to 1.82). In the multivariable mendelian randomisation analysis of breast cancer risk, strong evidence was found of a protective direct effect for larger body size in early life (0.59, 0.50 to 0.71), with less evidence of a direct effect of adult body size on this outcome (1.08, 0.93 to 1.27). Including age at menarche as an additional exposure provided weak evidence of a total causal effect (univariable mendelian randomisation odds ratio 0.98, 95% confidence interval 0.91 to 1.06) but strong evidence of a direct causal effect, independent of early life and adult body size (multivariable mendelian randomisation odds ratio 0.90, 0.85 to 0.95). No strong evidence was found of a causal effect of either early or later life measures on prostate cancer (early life body size odds ratio 1.06, 95% confidence interval 0.81 to 1.40; adult body size 0.87, 0.70 to 1.08).The findings suggest that the positive association between body size in childhood and risk of coronary artery disease and type 2 diabetes in adulthood can be attributed to individuals remaining large into later life. However, having a smaller body size during childhood might increase the risk of breast cancer regardless of body size in adulthood, with timing of puberty also putatively playing a role.