Key result
Genetic liability to major depressive disorder was causally associated with elevated triglyceride levels (OR 1.075; 95% CI 1.047-1.104; P<0.001), with waist-hip ratio mediating 69% of the effect.
Why the study?
The causal dynamics between major depressive disorder and dyslipidaemia remain elusive despite consistent observations of pronounced dyslipidaemia in MDD patients.
Do genetic proxies for major depressive disorder causally affect blood lipid levels?
Observational (n=5,237,893)
Yes
Do genetic proxies for major depressive disorder causally affect blood lipid levels?
Genetic liability to major depressive disorder is causally associated with elevated triglycerides, an effect largely mediated by waist-hip ratio.
May warrant lipid monitoring in MDD; leaves open whether adiposity-targeted interventions alter outcomes pending trials.
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.
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Sun et al. (2025) conducted an observational in Major depressive disorder and dyslipidaemia (n=5,237,893). Major depressive disorder (genetic liability) vs. Without major depressive disorder was evaluated on Triglycerides (TG) (OR 1.075, 95% CI 1.047 to 1.104, p=<0.001). Genetic liability to major depressive disorder was causally associated with elevated triglyceride levels (OR 1.075; 95% CI 1.047-1.104; P<0.001), with waist-hip ratio mediating 69% of the effect.
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