Mediators of the association between educational attainment and type 2 diabetes mellitus: a two-step multivariable Mendelian randomisation study

Abstract

Aims/hypothesis Type 2 diabetes mellitus is a major health burden disproportionately affecting those with lower educational attainment (EA). We aimed to obtain causal estimates of the association between EA and type 2 diabetes and to quantify mediating effects of known modifiable risk factors. Methods We applied two-step, two-sample multivariable Mendelian randomisation (MR) techniques using SNPs as genetic instruments for exposure and mediators, thereby minimising bias due to confounding and reverse causation. We leveraged summary data on genome-wide association studies for EA, proposed mediators (i.e. BMI, blood pressure, smoking, television watching) and type 2 diabetes. The total effect of EA on type 2 diabetes was decomposed into a direct effect and indirect effects through multiple mediators. Additionally, traditional mediation analysis was performed in a subset of the National Health and Nutrition Examination Survey 2013–2014. Results EA was inversely associated with type 2 diabetes (OR 0.53 for each 4.2 years of schooling; 95% CI 0.49, 0.56). Individually, the largest contributors were BMI (51.18% mediation; 95% CI 46.39%, 55.98%) and television watching (50.79% mediation; 95% CI 19.42%, 82.15%). Combined, the mediators explained 83.93% (95% CI 70.51%, 96.78%) of the EA–type 2 diabetes association. Traditional analysis yielded smaller effects but showed consistent direction and priority ranking of mediators. Conclusions/interpretation These results support a potentially causal protective effect of EA against type 2 diabetes, with considerable mediation by a number of modifiable risk factors. Interventions on these factors thus have the potential of substantially reducing the burden of type 2 diabetes attributable to low EA. Graphical abstract

Independent Associations of Education, Intelligence, and Cognition With Hypertension and the Mediating Effects of Cardiometabolic Risk Factors: A Mendelian Randomization Study

“…Moreover, several lifestyles, stress-related, and socioeconomic factors, such as watching TV, computer using, smoking initiation, insomnia, and total household income, were excluded from our mediation analyses due to their outstanding bidirectional causal associations with education, part of which are in line with the reverse causal associations reported by 1 mediation MR analysis between education and type 2 diabetes. 42 In our UVMR analyses, fasting glucose, moderate to vigorous physical activity, smoking heaviness, and coffee consumption manifested no causal effect on hypertension, which are highly consistent with 1 UVMR study investigating the causal lifestyle behaviors and cardiometabolic factors for hypertension. 5 It is worth noting that the interaction between sodium and potassium is a key component of blood pressure regulation, 23 and the sodium-potassium ratio has been suggested as a stronger predictor of blood pressure than either sodium or potassium excretion alone.…”

“…We then screened for mediators of the association between education and hypertension according to the following criteria: (1) There exists a causal association between education and the mediator, and the effect of education on the mediator should be unidirectional, because the validity of the mediation analyses may be affected if bidirectionality exists between them. 42 (2) The causal association consistently exists between the mediator and hypertension with or without adjustment for education; (3) Based on current scientific evidence, practically, the association between education and the mediator and the association between the mediator and hypertension should be in opposite directions. The detailed mediator selection process is shown in Figure 1 B.…”

Educational attainment and offspring birth weight: A bidirectional Mendelian randomization study

“…This approach additionally assumes that all selected IVs must be conditionally independent of the outcome, given all exposures and confounders ( Sanderson et al, 2019 ). Studies have found the associations between EA and body mass index (BMI) ( Liwin, 2022 ; Zhang et al, 2022 ; Zhao et al, 2022 ), alcoholic drinks per week ( Liu et al, 2019 ; Treur et al, 2021 ; Zhou et al, 2021 ). In addition, BMI of parents is well-established influencing factor for offspring birth weight according to both clinical observational and genetic association studies ( Vogelezang et al, 2020 ; Chen S. et al, 2021 ; Thompson et al, 2021 ; Aydogan Mathyk et al, 2022 ; Gootjes et al, 2022 ).…”

Causal effects of education attainment on oral and oropharyngeal cancer: New evidence from a meta-analysis and Mendelian randomization study

“…Years of schooling were converted and standardized, where each unit represented 4.2 years of schooling (1 standard deviation [SD] = 4.2 years). Based on published MR studies ( 17 , 18 ), a total of 268 single nucleotide polymorphisms (SNPs) were selected in our study for MR analysis ( Supplementary Table 2 ). According to previous studies, these SNPs accounted for 12% of the variation in EA among individuals ( 16 ).…”