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.

Childhood adiposity, adult body mass index, and disease in later life

“…The linked study by Richardson and colleagues (doi:10.1136/bmj.m1203) suggests that the effect of self-reported adiposity at age 10 on coronary artery disease and type 2 diabetes can be obviated by achieving and maintaining a normal body mass index (BMI) in adulthood 1. In addition, childhood adiposity might protect against breast cancer in women and might be unrelated to prostate cancer 1. The study used sophisticated and up-to-date mendelian randomization methods 1.…”

“…In addition, childhood adiposity might protect against breast cancer in women and might be unrelated to prostate cancer 1. The study used sophisticated and up-to-date mendelian randomization methods 1. Nevertheless, its findings need careful interpretation and contextualization before they can be applied to population health.…”

“…Taking the evidence together189 the possibility remains that childhood adiposity has little long term effect if followed by normal BMI later in adolescence,1 making the transition from childhood to adulthood a key point of intervention. Hitherto, much of the attention paid to early life influences has focused on the first 1000 days from conception10 and, despite intensive investigation for more than 30 years, the role of key indicators such as birth weight remains disputed 1112.…”

“…Hitherto, much of the attention paid to early life influences has focused on the first 1000 days from conception10 and, despite intensive investigation for more than 30 years, the role of key indicators such as birth weight remains disputed 1112. Less attention has been paid to adolescence,10 and specifically puberty,13 the physiological drivers of which could be relevant to observed sex and cancer specific effects of BMI 189…”

Mendel’s laws, Mendelian randomization and causal inference in observational data: substantive and nomenclatural issues

“…If data on earlier life drinking were available on a sufficiently large sample then MR could be carried out within the different reported categories of earlier drinking behaviour, with less confounding and bias than in conventional observational epidemiology. A detailed consideration of the meaning of MR estimates with respect to interventions at different stages of life and with different durations is available [4], and MR can provide reliable separation of some exposures acting at different periods of life, such as childhood and adulthood adiposity [83].…”