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 nondepressed persons.
METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 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 low-molecular-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 gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.
RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus 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.
| Original language | English |
|---|---|
| Pages (from-to) | 409-418 |
| Number of pages | 10 |
| Journal | Biological Psychiatry |
| Volume | 87 |
| Issue number | 5 |
| Early online date | 29 Aug 2019 |
| DOIs | |
| Publication status | Published - 1 Mar 2020 |
Funding
DOM-K works as a part-time clinical research consultant for Metabolon, Inc. BWJHP received (nonrelated) research funding from Janssen Research and Boehringer . All other authors report no biomedical financial interests or potential conflicts of interest. Rotterdam Study: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University , Rotterdam, Netherlands Organisation for the Health Research and Development, Research Institute for Diseases in the Elderly, Ministry of Education, Culture and Science, Ministry for Health, Welfare and Sports, European Commission (DG XII), and Municipality of Rotterdam. LLD study: LLD is a subcohort of the Lifelines cohort study, with additional measurements and sample collection funded by CardioVasculair Onderzoek Nederland (Grant No. 2012-03), European Science Council (Grant No. 715772 [to AZ]), and NWO (Vidi Grant No. 016.178.056 [to AZ] and Grant No. 864.13.013 [to JF]. SG holds scholarships from the Graduate School of Medical Sciences, University of Groningen. Netherlands Twin Register: Funding was obtained from the NWO and MagW/ZonMW (Grant Nos. 904-61-090 , 985-10-002 , 904-61-193,480-04-004 , l400-05-717 , Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192), BBMRI-NL (Grant No. 184.021.007), European Community’s Seventh Framework Programme (2007–2013) ENGAGE (HEALTH-F4-2007-201413), European Science Council (ERC Advanced Grant No. 230374), Rutgers University Cell and DNA Repository (National Institute of Mental Health Grant No. U24 MH068457-06), Avera Institute, and National Institutes of Health (Grant Nos. R01D0042157-01A and MH081802 , Grand Opportunity Grant No. 1RC2 MH089951 ). We gratefully acknowledge NWO Grant No. 480-15-001/674 : Netherlands Twin Register Repository: researching the interplay between genome and environment. ERF: The ERF study as a part of European Special Populations Research Network was supported by European Commission FP6 STRP Grant No. 018947 (LSHG-CT-2006-01947) and received funding from the European Community’s Seventh Framework Programme (2007–2013) HEALTH-F4-2007-201413 by the European Commission under the program “Quality of Life and Management of the Living Resources” of Fifth Framework Programme (Grant No. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from NWO and the Russian Foundation for Basic Research (Grant No. 047.017.043 ). The Maastricht Study: The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, Province of Limburg, Dutch Ministry of Economic Affairs (Grant No. 31O.041), Stichting De Weijerhorst , Pearl String Initiative Diabetes, Cardiovascular Center, Cardiovascular Research Institute Maastricht, School for Public Health and Primary Care, School for Nutrition, Toxicology and Metabolism, Stichting Annadal, and Health Foundation Limburg and by unrestricted grants from Janssen-Cilag B.V., Novo Nordisk Farma B.V., and Sanofi-Aventis Netherlands B.V. Leiden University Migraine Neuro-Analysis: Leiden University Migraine Neuro-Analysis is supported by the Netherlands Organisation for Health Research and Development (Vidi Grant No. 91711319 [to GMT]), Centre for Medical Systems Biology and Netherlands Consortium for Systems Biology, both within the framework of the Netherlands Genomics Initiative/NWO (to AMJMvdM), and Seventh Framework Programme EU project EUROHEADPAIN (Grant No. 602633 [to AMJMvdM and GMT]). This work was performed within the framework of the BBMRI Metabolomics Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government through Netherlands Organisation for Scientific Research ( NWO ) (Grant Nos. 184.021.007 and 184033111 ). 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 (Grant No. 10-000-1002 ) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). NEO study: The NEO study is supported by the participating Departments, Division, and Board of Directors of the Leiden University Medical Center, and by the Leiden University , Research Profile Area Vascular and Regenerative Medicine. DOM-K is supported by Dutch Science Organization (ZonMW-VENI Grant No. 916.14.023 ). CODAM: The initiation of the CODAM study was supported by NWO (Grant No. 940-35-034 ) and the Dutch Diabetes Research Foundation (Grant No. 98.901 ). The work of NV was supported through a grant from the Maastricht University Medical Center+. This work was performed within the framework of the BBMRI Metabolomics Consortium funded by BBMRI-NL, a research infrastructure financed by the Dutch government through Netherlands Organisation for Scientific Research (NWO) (Grant Nos. 184.021.007 and 184033111). 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 (Grant No. 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). CODAM: The initiation of the CODAM study was supported by NWO (Grant No. 940-35-034) and the Dutch Diabetes Research Foundation (Grant No. 98.901). The work of NV was supported through a grant from the Maastricht University Medical Center+. Leiden University Migraine Neuro-Analysis: Leiden University Migraine Neuro-Analysis is supported by the Netherlands Organisation for Health Research and Development (Vidi Grant No. 91711319 [to GMT]), Centre for Medical Systems Biology and Netherlands Consortium for Systems Biology, both within the framework of the Netherlands Genomics Initiative/NWO (to AMJMvdM), and Seventh Framework Programme EU project EUROHEADPAIN (Grant No. 602633 [to AMJMvdM and GMT]). NEO study: The NEO study is supported by the participating Departments, Division, and Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. DOM-K is supported by Dutch Science Organization (ZonMW-VENI Grant No. 916.14.023). The Maastricht Study: The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, Province of Limburg, Dutch Ministry of Economic Affairs (Grant No. 31O.041), Stichting De Weijerhorst, Pearl String Initiative Diabetes, Cardiovascular Center, Cardiovascular Research Institute Maastricht, School for Public Health and Primary Care, School for Nutrition, Toxicology and Metabolism, Stichting Annadal, and Health Foundation Limburg and by unrestricted grants from Janssen-Cilag B.V. Novo Nordisk Farma B.V. and Sanofi-Aventis Netherlands B.V. Netherlands Twin Register: Funding was obtained from the NWO and MagW/ZonMW (Grant Nos. 904-61-090, 985-10-002, 904-61-193,480-04-004, l400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192), BBMRI-NL (Grant No. 184.021.007), European Community's Seventh Framework Programme (2007–2013) ENGAGE (HEALTH-F4-2007-201413), European Science Council (ERC Advanced Grant No. 230374), Rutgers University Cell and DNA Repository (National Institute of Mental Health Grant No. U24 MH068457-06), Avera Institute, and National Institutes of Health (Grant Nos. R01D0042157-01A and MH081802, Grand Opportunity Grant No. 1RC2 MH089951). We gratefully acknowledge NWO Grant No. 480-15-001/674: Netherlands Twin Register Repository: researching the interplay between genome and environment. ERF: The ERF study as a part of European Special Populations Research Network was supported by European Commission FP6 STRP Grant No. 018947 (LSHG-CT-2006-01947) and received funding from the European Community's Seventh Framework Programme (2007–2013) HEALTH-F4-2007-201413 by the European Commission under the program “Quality of Life and Management of the Living Resources” of Fifth Framework Programme (Grant No. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from NWO and the Russian Foundation for Basic Research (Grant No. 047.017.043). Rotterdam Study: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organisation for the Health Research and Development, Research Institute for Diseases in the Elderly, Ministry of Education, Culture and Science, Ministry for Health, Welfare and Sports, European Commission (DG XII), and Municipality of Rotterdam. LLD study: LLD is a subcohort of the Lifelines cohort study, with additional measurements and sample collection funded by CardioVasculair Onderzoek Nederland (Grant No. 2012-03), European Science Council (Grant No. 715772 [to AZ]), and NWO (Vidi Grant No. 016.178.056 [to AZ] and Grant No. 864.13.013 [to JF]. SG holds scholarships from the Graduate School of Medical Sciences, University of Groningen. See Supplement 1 for BBMRI-NL Metabolomics Consortium collaborators and their affiliations. We thank the BBMRI-NL Metabolomics Consortium (see Supplement 1). The authors of the NEO study thank all participants, all participating general practitioners for inviting eligible participants, all research nurses for data collection, and the NEO study group: Pat van Beelen, Petra Noordijk, and Ingeborg de Jonge for coordination, laboratory, and data management. The authors of the ERF study thank all study participants and their relatives; general practitioners and neurologists for their contributions; and P. Veraart for help in genealogy, J. Vergeer for supervision of the laboratory work, and P. Snijders for help in data collection. The authors of the Rotterdam Study thank the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. DOM-K works as a part-time clinical research consultant for Metabolon, Inc. BWJHP received (nonrelated) research funding from Janssen Research and Boehringer. All other authors report no biomedical financial interests or potential conflicts of interest.
| Funders | Funder number |
|---|---|
| Avera Institute | |
| BBMRI-NL | |
| BBMRI-NL Metabolomics Consortium | |
| Cardiovasculair Onderzoek Nederland | 2012-03 |
| Cardiovascular Research Institute Maastricht | |
| Dutch Science Organization | |
| Dutch government through Netherlands Organisation for Scientific Research | |
| European Science Council | 715772 |
| Ingeborg de Jonge | |
| Janssen Research and Boehringer | |
| Janssen-Cilag B.V. Novo Nordisk Farma B.V. | |
| Leiden University Migraine Neuro-Analysis | |
| Maastricht University Medical Center+ | |
| Ministry of Education, Culture and Science, Ministry for Health, Welfare and Sports, European Commission | |
| Netherlands Organisation for the Health Research and Development, Research Institute for Diseases in the Elderly | |
| Pearl String Initiative Diabetes, Cardiovascular Center | |
| Quality of Life and Management of the Living Resources” of Fifth Framework Programme | QLG2-CT-2002-01254 |
| Spinozapremie | 56-464-14192 |
| ZonMW-VENI | 916.14.023 |
| National Institutes of Health | 1RC2 MH089951, MH081802, 480-15-001/674, R01D0042157-01A |
| National Institute of Mental Health | U24MH068457 |
| Janssen Pharmaceuticals | |
| Seventh Framework Programme | |
| Rutgers, The State University of New Jersey | |
| European Commission | |
| European Research Council | 230374 |
| Universiteit Leiden | |
| Rijksuniversiteit Groningen | 940-35-034 |
| ZonMw | 91711319, 10-000-1002 |
| Erasmus Universiteit Rotterdam | |
| Russian Foundation for Basic Research | 047.017.043 |
| Erasmus Medisch Centrum | |
| Diabetes Fonds | 98.901 |
| Ministerie van Economische Zaken | 31O.041 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 016.178.056, 184033111, 864.13.013, 904-61-090, 904-61-193,480-04-004, 985-10-002, 184.021.007, l400-05-717 |
| Novo Nordisk | |
| Seventh Framework Programme | 602633, HEALTH-F4-2007-201413 |
| Sixth Framework Programme | 018947, LSHG-CT-2006-01947 |
| Leids Universitair Medisch Centrum | |
| European Regional Development Fund |
Keywords
- Biomarkers
- Cardiovascular
- Depression
- Metabolites
- Metabolomics
- Pooled analysis
Cohort Studies
- Netherlands Twin Register (NTR)
