eLife (Feb 2021)
DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
- Eilis Hannon,
- Emma L Dempster,
- Georgina Mansell,
- Joe Burrage,
- Nick Bass,
- Marc M Bohlken,
- Aiden Corvin,
- Charles J Curtis,
- David Dempster,
- Marta Di Forti,
- Timothy G Dinan,
- Gary Donohoe,
- Fiona Gaughran,
- Michael Gill,
- Amy Gillespie,
- Cerisse Gunasinghe,
- Hilleke E Hulshoff,
- Christina M Hultman,
- Viktoria Johansson,
- René S Kahn,
- Jaakko Kaprio,
- Gunter Kenis,
- Kaarina Kowalec,
- James MacCabe,
- Colm McDonald,
- Andrew McQuillin,
- Derek W Morris,
- Kieran C Murphy,
- Colette J Mustard,
- Igor Nenadic,
- Michael C O'Donovan,
- Diego Quattrone,
- Alexander L Richards,
- Bart PF Rutten,
- David St Clair,
- Sebastian Therman,
- Timothea Toulopoulou,
- Jim Van Os,
- John L Waddington,
- Wellcome Trust Case Control Consortium (WTCCC),
- CRESTAR consortium,
- Patrick Sullivan,
- Evangelos Vassos,
- Gerome Breen,
- David Andrew Collier,
- Robin M Murray,
- Leonard S Schalkwyk,
- Jonathan Mill
Affiliations
- Eilis Hannon
- ORCiD
- University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom
- Emma L Dempster
- University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom
- Georgina Mansell
- ORCiD
- University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom
- Joe Burrage
- University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom
- Nick Bass
- Division of Psychiatry, University College London, London, United Kingdom
- Marc M Bohlken
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan, Utrecht, Netherlands
- Aiden Corvin
- Department of Psychiatry and Neuropsychiatric Genetics Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, St. James Hospital, Dublin, Ireland
- Charles J Curtis
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom; NIHR BioResource Centre Maudsley, South London and Maudsley NHS Foundation Trust (SLaM), King’s College London, London, United Kingdom
- David Dempster
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- Marta Di Forti
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom; South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom; National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre, South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom
- Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- Gary Donohoe
- Centre for Neuroimaging and Cognitive Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland
- Fiona Gaughran
- Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom; National Psychosis Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom
- Michael Gill
- Department of Psychiatry and Neuropsychiatric Genetics Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
- Amy Gillespie
- Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom; Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
- Cerisse Gunasinghe
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- Hilleke E Hulshoff
- Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
- Christina M Hultman
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Viktoria Johansson
- Department of Medical Epidemiology and Biostatistics Sweden, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Stockholm, Sweden
- René S Kahn
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States
- Jaakko Kaprio
- ORCiD
- Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland
- Gunter Kenis
- Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
- Kaarina Kowalec
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; College of Pharmacy, University of Manitoba, Winnipeg, Canada
- James MacCabe
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- Colm McDonald
- Centre for Neuroimaging and Cognitive Genomics (NICOG), School of Medicine, National University of Ireland Galway, Galway, Ireland
- Andrew McQuillin
- ORCiD
- Division of Psychiatry, University College London, London, United Kingdom; Division of Psychiatry, University College London, London, United Kingdom
- Derek W Morris
- Centre for Neuroimaging and Cognitive Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland
- Kieran C Murphy
- Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland
- Colette J Mustard
- ORCiD
- Division of Biomedical Sciences, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, United Kingdom
- Igor Nenadic
- Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany; Department of Psychiatry and Psychotherapy, Philipps University Marburg/ Marburg University Hospital UKGM, Marburg, Germany
- Michael C O'Donovan
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom
- Diego Quattrone
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom; South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom
- Alexander L Richards
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom
- Bart PF Rutten
- ORCiD
- Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
- David St Clair
- The Institute of Medical Sciences, Univeristy of Aberdeen, Aberdeen, United Kingdom
- Sebastian Therman
- ORCiD
- Department of Public Health Solutions, Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland
- Timothea Toulopoulou
- Department of Psychology and National Magnetic Resonance Research Center (UMRAM), Aysel Sabuncu Brain Research Centre (ASBAM), Bilkent University, Ankara, Turkey
- Jim Van Os
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
- John L Waddington
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Wellcome Trust Case Control Consortium (WTCCC)
- CRESTAR consortium
- Patrick Sullivan
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Evangelos Vassos
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom
- Gerome Breen
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom; NIHR BioResource Centre Maudsley, South London and Maudsley NHS Foundation Trust (SLaM), King’s College London, London, United Kingdom
- David Andrew Collier
- Neuroscience Genetics, Eli Lilly and Company, Surrey, United Kingdom
- Robin M Murray
- Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, United Kingdom
- Leonard S Schalkwyk
- School of Life Sciences, University of Essex, Colchester, United Kingdom
- Jonathan Mill
- ORCiD
- University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom
- DOI
- https://doi.org/10.7554/eLife.58430
- Journal volume & issue
-
Vol. 10
Abstract
We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Keywords
