A methylome-wide association study of major depression with out-of-sample case–control classification and trans-ancestry comparison

Major depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation may be associated with the condition. However, previous DNA methylation studies have, so far, not been widely replicated, suggesting a need for larger meta-analysis studies. Here we conducted a meta-analysis of methylome-wide association analysis for lifetime MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1,846 controls). We identified 15 CpG sites associated with lifetime MD with methylome-wide significance. The methylation score created using the methylome-wide association analysis summary statistics was significantly associated with MD status in an out-of-sample classification analysis (area under the curve 0.53). Methylation score was also associated with five inflammatory markers, with the strongest association found with tumor necrosis factor beta. Mendelian randomization analysis revealed 23 CpG sites potentially causally linked to MD, with 7 replicated in an independent dataset. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system.

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Publication Details

Journal
Nature Mental Health
Published
2025-09-16
DOI
https://doi.org/10.1038/s44220-025-00486-4
Citations
3
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
2.42

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article

A methylome-wide association study of major depression with out-of-sample case–control classification and trans-ancestry comparison

Louise Arseneault, Antoine Weihs, Jaakko A. Kaprio, Helen L. Fisher et al.
3 citations
Nature Mental Health
Epigenetics and DNA Methylation
2.42
article

A methylome-wide association study of major depression with out-of-sample case–control classification and trans-ancestry comparison

Louise Arseneault, Antoine Weihs, Jaakko A. Kaprio, Helen L. Fisher, Danni A. Gadd, Andrew Mark McIntosh, Kuan-Chen Lu, Jade Martins, Klaus Peter Berger, Henry Völzke, Po‐Hsiu Kuo, Nicholas G. Martin, Hugh Mulcahy, Miruna C. Barbu, Josef Frank, Elisabeth B. Binder, Eilis J. Hannon, Ellen Greimel, Joe Burrage, Natan Yusupov, Darina Czamara, Verena Pehl, Doretta Caramaschi, Therese M. Murphy, Tzu‐Pin Lu, Rosie M. Walker, Avshalom Caspi, Antje‐Kathrin Allgaier, Susanne L. Meinert, Evelyn Dilkes, Stella Iurato, M. Barber, Pau Navarro, Johannes Kopf‐Beck, Kathryn L. Evans, Ryan Arathimos, Hans Jörgen Grabe, Sarah E. Harris, Erin C. Dunn, Qingqin S. Li, Miina Ollikainen, Xueyi Shen, Cathryn M. Lewis, Lisa Feldmann, Charlotte Piechaczek, Floris Huider, Jonathan S. Mill, Teemu Palviainen, Tellervo Korhonen, Annemarie Luise Kühn, Gerd Schulte‐Körne, Chloe C. Y. Wong, Meena Kumari B, Frederike Stein, Naomi R. Wray, Udo Dannlowski, Tilo T. J. Kircher, H. W. Casey, Gemma Shireby, Eleanor Davyson, Simon R. Cox, Friederike Sophie David, Jenny van Dongen, Jordana T. Bell, Dorret Irene Boomsma, Georg Homuth, Terrie E. Moffitt, Alexander Teumer, Ricardo Costeira, Fabian Streit, Marisol Herrera-Rivero, Mark J. Adams, Aline D. Scherff, Anna Dearman, Alicia M. Schowe, David M. Howard, Andreas J. Forstner, Franz Joseph Freisleder, Edel McDermott
article en
3 citations

Abstract

Major depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation may be associated with the condition. However, previous DNA methylation studies have, so far, not been widely replicated, suggesting a need for larger meta-analysis studies. Here we conducted a meta-analysis of methylome-wide association analysis for lifetime MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1,846 controls). We identified 15 CpG sites associated with lifetime MD with methylome-wide significance. The methylation score created using the methylome-wide association analysis summary statistics was significantly associated with MD status in an out-of-sample classification analysis (area under the curve 0.53). Methylation score was also associated with five inflammatory markers, with the strongest association found with tumor necrosis factor beta. Mendelian randomization analysis revealed 23 CpG sites potentially causally linked to MD, with 7 replicated in an independent dataset. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system.

Nature Mental HealthVol. 3(10)
University College Dublin (IE), University of Essex (GB), NHS Lothian (GB), Roslin Institute (GB), University of Bonn (DE), Harvard University (US), Philipps University of Marburg (DE), The University of Queensland (AU), National Taiwan University (TW), Duke University (US), Forschungszentrum Jülich (DE), King's College London (GB), QIMR Berghofer Medical Research Institute (AU), Heidelberg University (DE), University of Münster (DE), University of Exeter (GB), Universitätsmedizin Greifswald (DE), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), University Hospital Heidelberg (DE), Edinburgh Cancer Research (GB), Center for Child and Family Health (US), LMU Klinikum (DE), Knorr-Bremse (Germany) (DE), University of Oxford (GB), Universität der Bundeswehr München (DE), Massachusetts General Hospital (US), Roche Pharma AG (Germany) (DE), Minerva Foundation (FI), Central Institute of Mental Health (DE), NeuroDevelopment Center (US), Brain (Germany) (DE), St. Vincent's University Hospital (IE), German Centre for Cardiovascular Research (DE), National Taiwan University Hospital (TW), Institute for Molecular Medicine Finland (FI), Institute for Social and Economic Research (GB), Technological University Dublin (IE), Max Planck Institute of Psychiatry (DE), Janssen (United States) (US), Institute of Genetics and Cancer (GB), University College London (GB), Ludwig-Maximilians-Universität München (DE), Vrije Universiteit Amsterdam (NL), University of Edinburgh (GB)
Taiwan Biobank, Boston Scientific Corporation, National Alliance for Research on Schizophrenia and Depression, University of Essex, Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, Scottish Government, Understanding Society, UK Research and Innovation, Max-Planck-Förderstiftung, UCD Foundation, National Institute for Health and Care Research, Department of Health and Social Care, Scottish Funding Council, Age UK, King's College London, European Commission, University of Bristol, Deutsche Forschungsgemeinschaft, Koninklijke Nederlandse Akademie van Wetenschappen, Bundesministerium für Bildung und Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Jacobs Foundation, Max-Planck-Gesellschaft, Westfälische Wilhelms-Universität Münster, Versus Arthritis, Centre for Cognitive Ageing and Cognitive Epidemiology, Universität Greifswald, Directorate for Biological Sciences, Chief Scientist Office, Scottish Government Health and Social Care Directorate, NIHR Maudsley Biomedical Research Centre, Medical Research Council, Biotechnology and Biological Sciences Research Council, Economic and Social Research Council, Menzies Centre for Australian Studies, King's College London, University of London, National Health and Medical Research Council, National Institute of Child Health and Human Development
Openalex Percentile: Top 10%
Epigenetics and DNA Methylation
2.42
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