Educational level as a cause of type 2 diabetes mellitus: Caution from triangulation of observational and genetic evidence

Abstract Background Education might be causal to type 2 diabetes mellitus (T2DM). We triangulated cohort and genetic evidence to consolidate the causality between education and T2DM. Methods We obtained observational evidence from the English Longitudinal Study of Ageing (ELSA). Self-reporting educational attainment was categorised as high (post-secondary and higher), middle (secondary), and low (below secondary or no academic qualifications) in 6,787 community-dwelling individuals aged ≥50 years without diabetes at ELSA wave 2, who were followed until wave 8 for the first diabetes diagnosis. Additionally, we performed two-sample Mendelian randomisation (MR) using an inverse-variance weighted (IVW), MR-Egger, weighted median (WM), and weighted mode-based estimate (WMBE) method. Steiger filtering was further applied to exclude single-nucleotide polymorphisms (SNPs) that were correlated with an outcome (T2DM) stronger than exposure (education attainment). Results We observed 598 new diabetes cases after 10.4 years of follow-up. The adjusted hazard ratios (95%CI) of T2DM were 1.20 (0.97-1.49) and 1.58 (1.28-1.96) in the middle- and low-education groups, respectively, compared to the high-education group. Low education was also associated with increased glycated haemoglobin levels. Psychosocial resources, occupation, and health behaviours fully explained these inverse associations. In the MR analysis of 210 SNPs (R2=0.0161), the odds ratio of having T2DM per standard deviation-decreasing years (4.2 years) of schooling was 1.33 (1.01-1.75; IVW), 1.23 (0.37-4.17; MR-Egger), 1.56 (1.09-2.27; WM), and 2.94 (0.98-9.09; WMBE). However, applying Steiger filtering attenuated most MR results toward the null. Conclusions Our inconsistent findings between cohort and genetic evidence did not support the causality between education and T2DM. Key messages What is already known on this subject? -Several pieces of evidence suggested that education attainment might play a causal role in the occurrence of T2DM. What does this study add? -Our observational evidence suggested no direct impact of education on the risk of T2DM. The observed inverse associations were mediated through insufficient psychosocial resources, low occupation class, and unhealthy behaviours due to low education. -In contrast, the genetic evidence suggested no causal association between education and the risk of T2DM. Notably, the significant associations from our genetic evidence resulted from the invalid genetic instrument used in the analysis. -The observational and genetic evidence was inconsistent; therefore, our triangulated evidence did not support a causal role of education in the occurrence of T2DM.