Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls

Abstract

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and non-depressed persons. Methods: Nine Dutch cohorts were included, comprising 10,145 controls and 5,283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids and lowmolecular-weight metabolites, 98 lipid composition and particle concentration measures of lipoprotein subclasses and 81 lipid and fatty acids ratios. For each metabolite measure logistic regression analyses adjusted for sex, age, smoking, fasting status and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. Results: Twenty-one of the 51 lipids, fatty acids and low-molecular-weight metabolites were significantly related to depression (false discovery rate q<0.05). Higher levels of apolipoprotein B, Very Low Density Lipoprotein (VLDL)-cholesterol, triglycerides, diglycerides, total and mono-unsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine, and lower levels of High Density Lipoprotein (HDL)-cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift towards less HDL and more VLDL and triglycerides particles in depression. Associations appeared generally consistent across sex, age and body mass index strata, and across cohorts with depressive diagnoses vs. symptoms. Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity. and 184033111. We would like to acknowledge the BBMRI-NL metabolomics consortium (Supplement 16). Netherlands Study of Depression and Anxiety (NESDA): The infrastructure for the NESDA study www.nesda.nl is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (

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