Causal relationships between blood lipids and major psychiatric disorders: Univariable and multivariable mendelian randomization analysis

Abstract

Background Whether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders. Methods Univariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10− 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium. Results We observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85–0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71–0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003–1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74–0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD. Conclusions Our results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.

Outcomes of Patients with Normal LDL-Cholesterol at Admission for Acute Coronary Syndromes: Lower Is Not Always Better

“…What we also consider a novel finding in our study is a greater proportion of patients with psychological disorders requiring medical attention in the low LDL-C group. A recent study [24] found that higher LDL-C levels were associated with a lower risk of major depressive disorder (MDD), whereas one relatively recent case-control study found that higher LDL-C and total cholesterol levels and lower HDL-C levels were connected to anxiety disorder risk [25]. There are numerous gaps in our understanding of the role of cholesterol and its biosynthesis, so at this moment we could only suggest reasons for the described connection between "spontaneous" low LDL and psychological disorders in ACS patients [26].…”