Reassessing the relationship between major depressive disorder and blood lipids: a comprehensive Mendelian randomisation study.

Abstract

Background: Numerous studies have consistently demonstrated that a considerable proportion of patients with major depressive disorder (MDD) frequently exhibit pronounced dyslipidaemia. However, the causal dynamics between MDD and dyslipidaemia remain elusive.

Aims: To comprehensively disentangle the genetic causality between MDD and various phenotypes of blood lipids, thereby facilitating the advancement of management strategies for these conditions.

Methods: We conducted a two-sample univariable Mendelian randomisation (MR) analysis using different models, including the inverse variance weighted (IVW) method and causal analysis using the summary effect (CAUSE) estimates, as well as a multivariable MR analysis. This analysis used summary statistics from genome-wide association studies (GWAS) of MDD and five lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, total cholesterol and triglycerides (TG), encompassing 5 237 893 individuals of European and East Asian ancestries. For MDD, a total of 598 701 individuals were included, with 500 199 individuals of European ancestry (N_case=170 756, N_control=329 443) and 98 502 of East Asian ancestry (N_case=12 588, N_control=85 914). Lipid data were collected from 4 639 192 individuals through the Global Lipids Genetics Consortium (European, N=4 096 085; East Asian, N=543 107). Next, we used the two-step MR to explore the mediating factors between MDD and TG, and the risk factors affecting TG through MDD. Finally, we conducted a GWAS meta-analysis and enrichment analysis.

Results: In univariable MR, we observed a negative causal effect of low-density lipoprotein on MDD in both European populations (IVW: odds ratio (OR): 0.972, 95% confidence interval (CI) 0.947 to 0.998, p=0.037) and East Asian populations (IVW: OR: 0.928, 95% CI 0.864 to 0.997, p=0.042). Additionally, we identified a bidirectional causal relationship between TG and MDD, with TG having a causal effect on MDD (IVW: OR: 1.052, 95% CI 1.020 to 1.085, p=0.001) and MDD having a causal effect on TG (IVW: OR: 1.075, 95% CI 1.047 to 1.104, p<0.001). Multivariable MR analysis further supported the role of TG in MDD (OR: 1.205, 95% CI 1.034 to 1.405, p=0.017). CAUSE estimates indicated that the causal model of MDD on TG provided a better fit than the sharing model (p=0.003), while the association of TG on MDD was more likely due to horizontal correlated pleiotropy than causality. Mediation analyses revealed that waist-hip ratio (WHR) mediated 69% of the total causal effect of MDD on TG, while other identified risk factors exhibited lower mediating proportions either mediated through MDD (≤17%) or originating from MDD (≤29%). The GWAS meta-analysis highlighted potential pathways related to lipid processes and nucleosome assembling, with significant cell types identified in brain regions and liver tissues.

Conclusions: The findings indicate that genetic proxies of MDD are associated with elevated levels of TG, with WHR serving as a clinical indicator of the association. This suggests that interventions targeting WHR may be effective in reducing TG levels in patients with MDD.