Three-exposure MVMR including cigarettes per day.

The alcohol harm paradox, whereby low socioeconomic position (SEP) groups experience greater alcohol-related harms at a given level of alcohol consumption, is not yet fully understood. In observational studies, key drivers are correlated and share similar confounding structures. We used multivariable Mendelian randomization (MVMR) to estimate the direct causal effect of alcohol (drinks per week) and education (years of schooling) on multiple health outcomes, accounting for the effect of the other. Previously published genome-wide association summary (GWAS) statistics for drinks per week and years of schooling were used, and outcome summary statistics were generated from individual-level data from UK Biobank (N = 462,818). Inverse variance weighted analyses demonstrated evidence for direct effects of alcohol and education on liver diseases (alcoholic liver disease: alcohol OR = 50.19, 95% CI 19.35 to 130.21 and education OR = 0.27, 95% CI 0.14 to 0.53; other liver diseases: alcohol OR = 1.82, 95% CI 1.12 to 2.94 and education OR = 0.42, 95% CI 0.30 to 0.58), mental and behavioural disorders due to alcohol (alcohol OR = 12.89, 95% CI 7.46 to 22.27 and education OR = 0.51, 95% CI 0.35 to 0.75), and stroke (alcohol OR = 1.94, 95% CI 1.30 to 2.89 and education OR = 0.73, 95% CI 0.55 to 0.97). There was evidence for direct effects of education on depression, anxiety, influenza/pneumonia, and heart disease. In contrast, there was evidence of total (without considering the effect of education), but not direct, effects of alcohol on depression, influenza/pneumonia, epilepsy, and injuries. Although caution is required when interpreting these results, given weak instruments for alcohol, these results provide some evidence that the alcohol harm paradox is partially due to the protective effect of additional years of education. Replication with strong genetic instruments for drinks per week would be necessary to draw causal inferences.

酒精伤害悖论（alcohol harm paradox）尚未得到完全阐明：在既定饮酒水平下，社会经济地位（socioeconomic position, SEP）较低的群体所承受的酒精相关伤害反而更为严重。在观察性研究中，核心影响因素彼此相关且具有相似的混杂结构。本研究采用多变量孟德尔随机化（multivariable Mendelian randomization, MVMR）方法，评估饮酒量（每周饮酒杯数）与受教育年限对多种健康结局的直接因果效应，并控制二者间的相互影响。本研究采用既往已发表的针对每周饮酒杯数与受教育年限的全基因组关联研究汇总统计量（genome-wide association study summary statistics, GWAS），并基于英国生物银行（UK Biobank）的个体层面数据（样本量N=462,818）生成了结局汇总统计量。逆方差加权分析结果显示，饮酒量与受教育年限对下述疾病存在直接因果效应：肝病（酒精性肝病：饮酒比值比（Odds Ratio, OR）=50.19，95%置信区间（Confidence Interval, CI）=19.35~130.21；受教育年限OR=0.27，95%CI=0.14~0.53；非酒精性肝病：饮酒OR=1.82，95%CI=1.12~2.94；受教育年限OR=0.42，95%CI=0.30~0.58）、酒精所致精神与行为障碍（饮酒OR=12.89，95%CI=7.46~22.27；受教育年限OR=0.51，95%CI=0.35~0.75）以及脑卒中（饮酒OR=1.94，95%CI=1.30~2.89；受教育年限OR=0.73，95%CI=0.55~0.97）。研究同时证实，受教育年限对抑郁症、焦虑症、流感/肺炎以及心脏病存在直接因果效应。与之相反，饮酒对抑郁症、流感/肺炎、癫痫以及损伤仅存在总效应（未考虑受教育年限的影响），未发现其直接因果效应。尽管由于饮酒相关遗传工具变量较弱，对本研究结果的解读需保持谨慎，但本研究结果仍提供了一定证据，表明酒精伤害悖论的部分成因源于更长受教育年限所带来的保护作用。未来需使用针对每周饮酒杯数的强遗传工具变量开展重复研究，方可得出确切的因果推断结论。