Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
41069367
TITLE
A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison.
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.
© The Author(s) 2025.
DATE PUBLISHED
2025
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2024/01/12
accepted 2025/07/23
medline 2025/10/10 06:29
pubmed 2025/10/10 06:28
entrez 2025/10/10 04:44
pmc-release 2025/09/16
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Shen X Shen Xueyi X Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Barbu M Barbu Miruna M Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Caramaschi D Caramaschi Doretta D Faculty of Health and Life Sciences, Department of Psychology, University of Exeter, Exeter, UK.
Arathimos R Arathimos Ryan R Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Czamara D Czamara Darina D Department Genes and Environment, Max-Planck-Institute of Psychiatry, Munich, Germany.
David FS David Friederike S FS Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
Dearman A Dearman Anna A Institute for Social and Economic Research, University of Essex, Colchester, UK.
Dilkes E Dilkes Evelyn E Institute for Social and Economic Research, University of Essex, Colchester, UK.
Herrera-Rivero M Herrera-Rivero Marisol M Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
Huider F Huider Floris F Biological Psychology, Amsterdam Public Health Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Kühn L Kühn Luise L Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Lu KC Lu Kuan-Chen KC Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
Palviainen T Palviainen Teemu T Institute for Molecular Medicine Finland-FIMM, University of Helsinki, Helsinki, Finland.
Schowe AM Schowe Alicia M AM Ludwig-Maximilians-Universität, Graduate School of Systemic Neuroscience, Munich, Germany.
Shireby G Shireby Gemma G Institute of Education, University College London, London, UK.
Weihs A Weihs Antoine A German Centre for Neurodegenerative Diseases (DZNE), Greifswald, Germany.
Wong CCY Wong Chloe C Y CCY Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Davyson E Davyson Eleanor E School of Informatics, University of Edinburgh, Edinburgh, UK.
Casey H Casey Hannah H Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Adams MJ Adams Mark J MJ Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Allgaier AK Allgaier Antje-Kathrin AK Department of Human Sciences, University of the Bundeswehr Munich, Munich, Germany.
Barber M Barber Michael M MRC Human Genetics Unit, University of Edinburgh, Edinburgh, UK.
Burrage J Burrage Joe J Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Caspi A Caspi Avshalom A Departments of Psychology and Neuroscience, Psychiatry and Behavioral Sciences, and Institute for Genome Sciences and Policy, Duke University, Durham, NC USA.
Costeira R Costeira Ricardo R Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Dunn EC Dunn Erin C EC Department of Psychiatry, Harvard Medical School, Boston, MA USA.
Feldmann L Feldmann Lisa L German Center for Mental Health (DZPG), Partner Site Munich-Augsburg, Munich, Germany.
Frank J Frank Josef J Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Freisleder FJ Freisleder Franz J FJ kbo-Heckscher-Klinikum gGmbH, Munich, Germany.
Gadd DA Gadd Danni A DA Institute of Genetics and Cancer, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
Greimel E Greimel Ellen E German Center for Mental Health (DZPG), Partner Site Munich-Augsburg, Munich, Germany.
Hannon E Hannon Eilis E Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Harris SE Harris Sarah E SE Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Homuth G Homuth Georg G Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Howard DM Howard David M DM Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Iurato S Iurato Stella S Roche Diagnostics GmbH, Munich, Germany.
Korhonen T Korhonen Tellervo T Institute for Molecular Medicine Finland-FIMM, University of Helsinki, Helsinki, Finland.
Lu TP Lu Tzu-Pin TP Department of Public Health and Institute of Health Data Analytics and Statistics, National Taiwan University, Taipei, Taiwan.
Martin NG Martin Nicholas G NG Queensland Institute of Medical Research Berghofer, Brisbane, Queensland Australia.
Martins J Martins Jade J Decision Intelligence, Knorr-Bremse Services GmbH, Munich, Germany.
McDermott E McDermott Edel E Centre for Colorectal Disease, St Vincent's University Hospital, Dublin, Ireland.
Meinert S Meinert Susanne S Institute for Translational Neuroscience, University of Münster, Münster, Germany.
Navarro P Navarro Pau P The Roslin Institute, University of Edinburgh, Edinburgh, UK.
Ollikainen M Ollikainen Miina M Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Pehl V Pehl Verena V Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
Piechaczek C Piechaczek Charlotte C Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, LMU University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
Scherff AD Scherff Aline D AD German Center for Mental Health (DZPG), Partner Site Munich-Augsburg, Munich, Germany.
Stein F Stein Frederike F Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
Streit F Streit Fabian F German Center for Mental Health (DZPG), Partner Site Mannheim-Heidelberg-Ulm, Mannheim, Germany.
Teumer A Teumer Alexander A German Centre for Cardiovascular Research (DZHK), Greifswald, Germany.
Völzke H Völzke Henry H Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
van Dongen J van Dongen Jenny J Biological Psychology, Amsterdam Public Health Institute, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Walker RM Walker Rosie M RM Faculty of Health and Life Sciences, Department of Psychology, University of Exeter, Exeter, UK.
Yusupov N Yusupov Natan N International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
Arseneault L Arseneault Louise L Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Bell JT Bell Jordana T JT Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Berger K Berger Klaus K Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
Binder E Binder Elisabeth E Department Genes and Environment, Max-Planck-Institute of Psychiatry, Munich, Germany.
Boomsma DI Boomsma Dorret I DI Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Cox SR Cox Simon R SR Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
Dannlowski U Dannlowski Udo U Institute for Translational Psychiatry, University of Münster, Münster, Germany.
Evans KL Evans Kathryn L KL Institute for Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
Fisher HL Fisher Helen L HL ESRC Centre for Society and Mental Health, King's College London, London, UK.
Forstner AJ Forstner Andreas J AJ Centre for Human Genetics, University of Marburg, Marburg, Germany.
Grabe HJ Grabe Hans J HJ German Centre for Neurodegenerative Diseases (DZNE), Greifswald, Germany.
Kaprio J Kaprio Jaakko J Institute for Molecular Medicine Finland-FIMM, University of Helsinki, Helsinki, Finland.
Kircher T Kircher Tilo T Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
Kopf-Beck J Kopf-Beck Johannes J Department of Psychology, LMU Munich, Munich, Germany.
Kumari M Kumari Meena M Institute for Social and Economic Research, University of Essex, Colchester, UK.
Kuo PH Kuo Po-Hsiu PH Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan.
Li QS Li Qingqin S QS Neuroscience, Janssen Research and Development, Titusville, NJ USA.
Moffitt TE Moffitt Terrie E TE Departments of Psychology and Neuroscience, Psychiatry and Behavioral Sciences, and Institute for Genome Sciences and Policy, Duke University, Durham, NC USA.
Mulcahy H Mulcahy Hugh H School of Medicine, University College Dublin, Dublin, Ireland.
Murphy TM Murphy Therese M TM School of Biological, Health and Sports Sciences, Technological University Dublin, Dublin, Ireland.
Schulte-Körne G Schulte-Körne Gerd G German Center for Mental Health (DZPG), Partner Site Munich-Augsburg, Munich, Germany.
Mill J Mill Jonathan J Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Lewis CM Lewis Cathryn M CM Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
PGC MDD Working Group
Wray NR Wray Naomi R NR Department of Psychiatry, University of Oxford, Oxford, UK.
McIntosh AM McIntosh Andrew M AM Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Shen Xueyi X
Caramaschi Doretta D
Arathimos Ryan R
Czamara Darina D
David Friederike S FS
Dearman Anna A
Dilkes Evelyn E
Herrera-Rivero Marisol M
Huider Floris F
Kühn Luise L
Lu Kuan-Chen KC
Palviainen Teemu T
Schowe Alicia M AM
Shireby Gemma G
Weihs Antoine A
Wong Chloe C Y CCY
Adams Mark J MJ
Allgaier Antje-Kathrin AK
Barber Michael M
Burrage Joe J
Caspi Avshalom A
Costeira Ricardo R
Dunn Erin C EC
Feldmann Lisa L
Frank Josef J
Freisleder Franz J FJ
Greimel Ellen E
Hannon Eilis E
Homuth Georg G
Howard David M DM
Iurato Stella S
Korhonen Tellervo T
Lu Tzu-Pin TP
Martin Nicholas G NG
Martins Jade J
McDermott Edel E
Meinert Susanne S
Ollikainen Miina M
Pehl Verena V
Piechaczek Charlotte C
Scherff Aline D AD
Stein Frederike F
Streit Fabian F
Teumer Alexander A
Völzke Henry H
Yusupov Natan N
Arseneault Louise L
Bell Jordana T JT
Berger Klaus K
Binder Elisabeth E
Boomsma Dorret I DI
Dannlowski Udo U
Fisher Helen L HL
Forstner Andreas J AJ
Grabe Hans J HJ
Kaprio Jaakko J
Kircher Tilo T
Kopf-Beck Johannes J
Kumari Meena M
Kuo Po-Hsiu PH
Li Qingqin S QS
Moffitt Terrie E TE
Mulcahy Hugh H
Murphy Therese M TM
Schulte-Körne Gerd G
Lewis Cathryn M CM
van Dongen Jenny J
Wray Naomi R NR
McIntosh Andrew M AM
JOURNAL
VOLUME: 3
ISSUE: 10
TITLE: Nature. Mental health
ISOABBREVIATION: Nat Ment Health
YEAR: 2025
MONTH:
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 2731-6076
ISSNTYPE: Electronic
MEDLINE JOURNAL
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
DNA methylation
Depression
Epigenomics
Predictive markers
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
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