Multivariable Mendelian randomization to disentangle the alcohol 1 harm paradox.

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. Author SummaryIndividuals from lower socioeconomic position backgrounds tend to disproportionately experience alcohol-related physical and mental ill-health, despite reporting lower overall alcohol consumption than those from higher socioeconomic backgrounds. This is known as the alcohol harm paradox. One key difficulty in understanding this paradox is the methodological difficulty of establishing the relative contribution of multiple complex social behaviours. In this study, we used genetic variants associated with alcohol consumption and years of education to explore their direct effects on multiple health outcomes. The findings indicate that greater alcohol consumption and fewer years of education may each, independently increase the likelihood of developing various health conditions, including liver diseases, mental and behavioural disorders due to alcohol, and stroke. This may suggest that the alcohol harm paradox is due to the protective effect of additional years of education amongst those from higher socioeconomic position backgrounds, reducing their likelihood of developing the health conditions. However, these findings are preliminary and limited by various methodological issues, suggesting these findings should be interpreted with caution. Replication and further studies are needed.