Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, UK.
Int J Epidemiol. 2023 Apr 19;52(2):545-561. doi: 10.1093/ije/dyac159.
An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants.
In Cox regression models, parental BMI was instrumented by offspring BMI using an 'offspring as instrument' (OAI) estimation and by offspring BMI-related genetic variants in a 'proxy-genotype Mendelian randomization' (PGMR) estimation.
Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent-offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother-son) and 1.23 (95% CI: 1.16, 1.29; father-daughter).
Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them.
越来越多的人体重指数（BMI）被归类为超重或肥胖，已发表的研究对 BMI 增加是否对健康有益或有害存在分歧。我们应用并评估了两种跨代工具变量方法，以估计 UK Biobank 参与者的父母这一有大量死亡人数的队列中 BMI 对死亡率的平均因果效应。
在 Cox 回归模型中，使用“子女作为工具”（OAI）估计和“代理基因型孟德尔随机化”（PGMR）估计中子女 BMI 相关遗传变异对父母 BMI 进行工具变量处理。
在具有完整表型、基因型和协变量数据的 233361 名 UK Biobank 参与者的父母中进行了完全案例分析。PGMR 方法表明，BMI 每增加 1kg/m2，母亲的死亡率风险比为 1.02（95%CI：1.01，1.04），父亲的死亡率风险比为 1.04（95%CI：1.02，1.05）。OAI 方法给出了更高的估计值，这些值根据亲子配对而有所不同，范围从 1.08（95%CI：1.06，1.10；母亲-儿子）到 1.23（95%CI：1.16，1.29；父亲-女儿）。
两种方法都支持 BMI 升高与死亡率增加之间存在因果关系，但需要谨慎对待这些确切值的直接因果解释。OAI 方法中用于测量协变量的工具无效证据有限，PGMR 方法中则微不足道。这两种方法互补，可以用来研究平均潜在因果效应，因为它们之间的偏差预计会有所不同。
