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.

中文翻译：

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使用遗传变异来区分早期和晚期肥胖对疾病风险的影响：孟德尔随机化研究。

目的 评估生命早期的体型是否对晚年的疾病风险具有独立影响，或者其影响是否受成年期的体型调节。设计 两个样本单变量和多变量孟德尔随机化。设置 UK Biobank 前瞻性队列研究和四个大型全基因组关联研究 (GWAS) 联盟。参与者 453 169 名参与者注册了英国生物银行，以及来自不同 GWAS 财团的总计超过 700 000 人。暴露 测量成年期的体重指数（平均年龄 56.5 岁）和自我报告的 10 岁时感知的体型。主要结果测量 冠状动脉疾病、2 型糖尿病、乳腺癌和前列腺癌。结果 在生命早期具有较大的遗传预测体型与冠状动脉疾病的几率增加相关（除非另有说明，体型类别的每个变化的优势比为 1.49，95% 置信区间为 1.33 至 1.68）和 2 型糖尿病（2.32 , 1.76 到 3.05) 基于单变量孟德尔随机化分析。然而，基于多变量孟德尔随机化估计（冠状动脉疾病：1.02，0.86 至 1.22；2 型糖尿病：1.16，0.74 至 1.82），几乎没有发现直接影响（即，不是通过成人体型）的证据。在对乳腺癌风险的多变量孟德尔随机化分析中，发现了强有力的证据表明对生命早期较大的体型具有直接保护作用（0.59，0.50 至 0.71），而成人体型对这一结果的直接影响的证据较少（ 1.08, 0.93 比 1。27)。将初潮年龄作为额外的暴露提供了总因果效应的弱证据（单变量孟德尔随机优势比 0.98，95% 置信区间 0.91 至 1.06），但直接因果效应的有力证据，独立于早期生活和成人体型（多变量孟德尔随机优势比 0.90、0.85 至 0.95）。没有强有力的证据表明早期或晚期生活测量对前列腺癌的因果影响（早期身体尺寸优势比 1.06，95% 置信区间 0.81 至 1.40；成人身体尺寸 0.87，0.70 至 1.08）。结论 研究结果表明，儿童期体型与成年期冠状动脉疾病和 2 型糖尿病风险之间的正相关可归因于个体在以后的生活中仍然保持体型。然而，