Background Diets characterised by fast foods, snacks and ‘comfort foods’ are associated with an obvious threat to physical well-being, but they can also impact psychological health. Major depressive disorder (MDD) and chronic stress seem to be conditions particularly susceptible to unhealthy diets rich in fat and sugar, yet there is no evidence whether the relationship is causal. The aims of this study were to investigate whether the relationship of fat and sugar intake with MDD and cortisol was causal, and to shed light on the direction of this relationship.

Methods Two-sample Mendelian Randomisation (MR) analysis was conducted. Plasma cortisol levels were considered to be a proxy for chronic stress levels. Pathways between macronutrients and MDD/plasma cortisol were assessed by considering analysis in two directions: one with macronutrients as exposures and one with MDD/plasma cortisol as exposures. Summary-level data for all exposure and outcome variables was obtained from large-scale, non-overlapping GWASs in individuals of European ancestry. Random-effects inverse-variance weighted regression was used as the primary analytic method for genetic instruments with at least two single nucleotide polymorphisms (SNPs) available. As measures of effect size, odds ratios (OR) were reported for binary outcomes and standardised beta coefficients (β) for continuous outcomes. Two sets of genetic instruments were chosen: main analysis set included only genome-significant SNPs (p<1×10⁻⁸), while sensitivity analysis set included SNPs meeting a relaxed p-value threshold (p<5×10⁻⁶). Robust MR methods, such as MR-Egger, weighted median, weighted mode, MR-PRESSO and MR-RAPS, were used to assess potential violations of key MR assumptions. All statistical analyses were conducted in R (version 4.0.2) using the TwoSampleMR package.

Results Higher relative sugar intake was associated with lower risk of MDD. The results were significant in the main analysis, using inverse-variance weighted regression (β=0.786, 95% CI: 0.630–0.981), weighted median (β=0.743, 95% CI: 0.558–0.990) and RAPS (β=0.790, 95% CI: 0.656–0.953) methods, as well as in the sensitivity analysis, using inverse-variance weighted regression (β=0.553, 95% CI: 0.395–0.775), weighted median (β=0.518, 95% CI: 0.338–0.794) and RAPS (β=0.545, 95% CI: 0.400–0.742) methods. No other significant associations were found in either direction.

Conclusion Higher relative sugar intake might reduce the risk of MDD, but has no effect on chronic stress. There is no causal relationship between relative fat intake, MDD and chronic stress. One of the study’s limitation is possible ‘horizontal’ pleiotropy where the SNP influences the outcome through some pathway other than the exposure. Additionally, only European descent participants were analysed in the study.