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. 2022 Aug;65(8):1364-1374.
doi: 10.1007/s00125-022-05705-6. Epub 2022 Apr 28.

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

Jia Zhang  1   2 , Zekai Chen  1 , Katri Pärna  1   3 , Sander K R van Zon  4 , Harold Snieder  1 , Chris H L Thio  5
Affiliations

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

Jia Zhang et al. Diabetologia. 2022 Aug.

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.

Keywords: Educational attainment; Mediation; Mendelian randomisation; Type 2 diabetes.

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Figures

Fig. 1
Fig. 1
(a) MR-estimated effects of EA (per 4.2 years of schooling) on each mediator separately, presented as β/OR with 95% CI. (b) MR-estimated effects of each mediator separately on type 2 diabetes after MVMR adjustment for education, presented as β/OR with 95% CI. (c) MR-estimated effects of indirect effects of each mediator separately, by product of coefficients method with delta method-estimated 95% CIs. MR-estimated proportions mediated (%) are presented with 95% CIs. T2D, type 2 diabetes; TV, television
Fig. 2
Fig. 2
MR estimates of combined proportions mediated by multiple mediators, presented as percentages with 95% CIs. SI, smoking initiation (ever vs never); TV, television watching
See this image and copyright information in PMC

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