Genetically proxied educational attainment (EA) substantially reduces risk across six major cardiovascular outcomes — coronary artery disease, myocardial infarction, heart failure, atrial fibrillation, ischaemic stroke, and type 2 diabetes — with odds ratios ranging 0.61–0.78. Critically, joint multivariable Mendelian randomisation across 22 cardiometabolic risk factors revealed that 63–82% of EA's protection against CAD, heart failure, and T2DM operates through modifiable pathways, with atrial fibrillation fully mediated. Four protein loci (LMOD1, DAG1, CD40, MEGF9) showed shared genetic architecture between EA and CVD endpoints.
The finding reframes the education–heart disease gradient from a largely fixed social determinant into a predominantly biological problem amenable to clinical intervention. By isolating genetic instruments for education, the Mendelian randomisation design reduces confounding that plagues observational socioeconomic research — though residual pleiotropy and overlapping GWAS samples remain legitimate concerns. The 15–37% of risk unexplained by conventional cardiometabolic factors, especially for ischaemic stroke, implies parallel pathways — possibly psychosocial stress, healthcare access, or as-yet-unmeasured mediators — deserving separate investigation. The protein colocalisation findings are hypothesis-generating only at this stage. Practically, these results support targeting aggressive cardiometabolic risk factor management — blood pressure, lipids, glucose, BMI — in lower-education populations as a scalable equity intervention. However, as this is a preprint not yet peer-reviewed, the mediation percentages and protein findings require independent replication before informing clinical guidelines.