Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomisation study
Year: 2020
Type: article
Study design: Observational 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.
Source: BMJ
DOI: 10.1136/bmj.m1203
Institutions: University of Bristol, MRC Integrative Epidemiology Unit
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Awards: G1192034430, G1605161196, G2538597952, The Avon Longitudinal Study of Parents and Children (ALSPAC): A multi- generation, longitudinal resource focusing on life course health and well- being., G3696935633, G3831911591, The Avon Longitudinal Study for Parents and Children: An international resource for population genomic and lifecourse epidemiology. Core programme support 2014-2019., Statistical Methods for Improving Causal Analyses, Dissecting the molecular aetiology of complex traits using high dimensional omic data, G5562631338, G5850737185, G6050707053, G6689231961, Mendelian randomization to hypothesis-free causal inference, G7157845406, G7394402392, G7926763962, G7990456425, G801210579, G8201869620, G8502142660, Pleiotropy robust Mendelian randomization, G896001452
OpenAlex ID: W3011942165