Background: Susceptibility to type 2 diabetes mellitus (T2D) is driven by genetic and environmental risk factors. Dietary preferences are a modifiable and largely environmental risk factor for T2D. The role of diet in disease liability has been limited to observational and epidemiologic studies with mixed findings. Objective: To clarify the role of diet on susceptibility to T2D using genetic variants associated dietary preferences. Methods: We collected genome-wide association data for 38 dietary preference traits plus T2D and 21 related cardiometabolic traits. We performed Mendelian randomization (MR) using genetic variants to test causal hypotheses between diet as the exposure and T2D or cardiometabolic traits as outcomes using univariable and multivariable methods along with the MR Robust Adjusted Profile Score (MR-RAPS) approach to increase power. We performed mediation analyses to evaluate the effects of dietary preferences on T2D to elucidate potential causal graphs and estimate the effects of dietary preferences mediated by potential mediators. Results: We report 17 significant relationships between dietary preferences and T2D or a cardiometabolic risk factor (Bonferroni-corrected P < 5.99 x 10-5), including that higher intake of cheese, dried fruit, muesli, or fat-based spreads protected against T2D. We detected 7 additional associations (Bonferroni-corrected P < 1 x 10-4), with inclusion of additional genetic variants in MR-RAPS analysis. In multivariable MR, we discovered that body mass index (BMI) was a common, shared mediator for many of these observed associations. In mediation analysis, we confirmed that substantial proportions of the protective effects of cheese, dried fruit and muesli intakes on T2D were mediated by BMI. We further observed that educational attainment was an additional mediator exclusively for muesli intake-T2D association. Conclusions: Our results provide genetic evidence supporting a link between diet and body weight, and are in line with observation of obesity and T2D in individuals and their specific preferences for food.

The authors have declared no competing interest.

This study did not receive any funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All the data used in this work were de-identified summary statistics data from genome-wide association studies. The publicly available GWAS summary-level datasets were made publicly available after approval by the institutional ethical committees of the different consortia. The most of the GWAS summary-level datasets used in the study were publicly available. The GWAS summary-level data for dietary composition (relative macronutrient intakes) was requested at https://www.thessgac.org/. The GWAS summary-level data for dietary habits and food liking traits were publicly available at https://www.kp4cd.org/dataset_downloads/t2d and The NHGRI-EBI GWAS Catalog website (https://www.ebi.ac.uk/gwas/publications/35585065), respectively. The GWAS summary-level data for type 2 diabetes mellitus was obtained from MVP study via request. The GWAS summary-level datasets for glycemic traits were publicly available at https://www.magicinvestigators.org/. The GWAS summary-level datasets for lipid traits were publicly available at http://csg.sph.umich.edu/willer/public/glgc-lipids2021/. The GWAS summary-level datasets for anthropometric traits were publicly available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files. The GWAS summary-level datasets for abdominal organ MRI, liver enzymes and physical activity related traits were publicly available at The NHGRI-EBI GWAS Catalog website (https://www.ebi.ac.uk/gwas/publications/34128465, https://www.ebi.ac.uk/gwas/publications/33547301, https://www.ebi.ac.uk/gwas/publications/33972514, https://www.ebi.ac.uk/gwas/publications/36071172). The GWAS summary-level data for educational attainment was obtained via request at The NHGRI-EBI GWAS Catalog website (https://www.ebi.ac.uk/gwas/studies/GCST003676).

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