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

Jia Zhang, Zekai Chen, Katri Pärna, Sander K.R. van Zon, Harold Snieder, Chris H.L. Thio*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)1364-1374
Number of pages11
Early online date28-Apr-2022
Publication statusPublished - Aug-2022


  • Educational attainment
  • Mediation
  • Mendelian randomisation
  • Type 2 diabetes

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