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

Abstract

Objective: 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.

Design: Two sample univariable and multivariable mendelian randomisation.

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

Participants: 453 169 participants enrolled in UK Biobank and a combined total of more than 700 000 people from different GWAS consortiums.

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, type 2 diabetes, breast cancer, and prostate cancer.

Results: 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).

Conclusions: 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.

Fig 1

Directed acyclic graphs depicting three possible scenarios that could explain a causal effect between body size at age 10 years and disease outcomes in adulthood. (Top) Early life body size has an indirect effect on disease risk only through body size in adulthood, (middle) early life body size has a direct effect on disease risk independent of body size in adulthood, and (bottom) early life body size exerts both direct and indirect effects on disease risk in adulthood

Fig 2

Receiver operator characteristic curves to compare the predictive capability of early life and adult body size scores across three time points in Avon Longitudinal Study of Children and Parents (ALSPAC). (Top) Mean age 9.9 years in the ALSPSAC offspring; (middle) mean age 17.9 years in the ALSPAC offspring; and (bottom) mean age 50.8 years in the ALSPAC mothers. Body mass index in the ALSPAC cohort was dichotomised based on the 85th centile in all analyses. AUC=area under curve

Fig 3

Bidirectional Manhattan plot to illustrate genetic variants across the genome associated with (top) body size in early life (age 10 years) and body size in adulthood (bottom). Yellow points highlight effects that provided stronger evidence of association with early life body size, whereas purple points highlight effects more strongly associated with adult body size. These genetic loci have been annotated based on the nearest protein coding gene to the top associated variant

Fig 4

Forest plot illustrating direct and indirect effects for genetically predicted body size in early life (age 10 years) on four different disease outcomes (coronary artery disease, type 2 diabetes, breast cancer, and prostate cancer). Filled and open diamonds represent effects from univariable and multivariable mendelian randomisation (MR) analyses, respectively. Estimates are displayed as odds ratios with 95% confidence intervals