DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia-Reference-Cited by-同舟云学术

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Published:2021-02-26 Issue: Volume:10 Page:
ISSN:2050-084X
Container-title:eLife
language:en
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Author:

Hannon Eilis¹^ORCID,Dempster Emma L¹,Mansell Georgina¹^ORCID,Burrage Joe¹,Bass Nick²,Bohlken Marc M³,Corvin Aiden⁴,Curtis Charles J⁵⁶,Dempster David⁵,Di Forti Marta⁵⁷⁸,Dinan Timothy G⁹,Donohoe Gary¹⁰,Gaughran Fiona¹¹¹²,Gill Michael¹³,Gillespie Amy¹¹¹⁴,Gunasinghe Cerisse⁵,Hulshoff Hilleke E¹⁵,Hultman Christina M¹⁶,Johansson Viktoria¹⁷¹⁸,Kahn René S¹⁹²⁰,Kaprio Jaakko²¹²²^ORCID,Kenis Gunter²³,Kowalec Kaarina¹⁶²⁴,MacCabe James⁵,McDonald Colm²⁵,McQuillin Andrew²²^ORCID,Morris Derek W¹⁰,Murphy Kieran C²⁶,Mustard Colette J²⁷^ORCID,Nenadic Igor²⁸²⁹,O'Donovan Michael C³⁰,Quattrone Diego⁵⁷,Richards Alexander L³⁰,Rutten Bart PF³¹^ORCID,St Clair David³²,Therman Sebastian³³^ORCID,Toulopoulou Timothea³⁴,Van Os Jim¹⁹,Waddington John L³⁵,Sullivan Patrick¹⁶³⁶,Vassos Evangelos⁵,Breen Gerome⁵⁶,Collier David Andrew³⁷,Murray Robin M³⁸,Schalkwyk Leonard S³⁹,Mill Jonathan¹^ORCID, ,

Affiliation:

1. University of Exeter Medical School, University of Exeter, Barrack Road, Exeter, United Kingdom

2. Division of Psychiatry, University College London, London, United Kingdom

3. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan, Utrecht, Netherlands

4. Department of Psychiatry and Neuropsychiatric Genetics Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, St. James Hospital, Dublin, Ireland

5. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom

6. NIHR BioResource Centre Maudsley, South London and Maudsley NHS Foundation Trust (SLaM), King’s College London, London, United Kingdom

7. South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom

8. 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

9. APC Microbiome Ireland, University College Cork, Cork, Ireland

10. Centre for Neuroimaging and Cognitive Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland

11. Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, United Kingdom

12. National Psychosis Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom

13. Department of Psychiatry and Neuropsychiatric Genetics Research Group, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland

14. Department of Psychiatry, Medical Sciences Division, University of Oxford, Oxford, United Kingdom

15. Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands

16. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

17. Department of Medical Epidemiology and Biostatistics Sweden, Karolinska Institutet, Stockholm, Sweden

18. Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Stockholm, Sweden

19. Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands

20. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, United States

21. Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland

22. Department of Public Health, University of Helsinki, Helsinki, Finland

23. Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands

24. College of Pharmacy, University of Manitoba, Winnipeg, Canada

25. Centre for Neuroimaging and Cognitive Genomics (NICOG), School of Medicine, National University of Ireland Galway, Galway, Ireland

26. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland

27. Division of Biomedical Sciences, Institute of Health Research and Innovation, University of the Highlands and Islands, Inverness, United Kingdom

28. Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany

29. Department of Psychiatry and Psychotherapy, Philipps University Marburg/ Marburg University Hospital UKGM, Marburg, Germany

30. MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom

31. Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands

32. The Institute of Medical Sciences, Univeristy of Aberdeen, Aberdeen, United Kingdom

33. Department of Public Health Solutions, Mental Health Unit, National Institute for Health and Welfare, Helsinki, Finland

34. Department of Psychology and National Magnetic Resonance Research Center (UMRAM), Aysel Sabuncu Brain Research Centre (ASBAM), Bilkent University, Ankara, Turkey

35. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

36. Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States

37. Neuroscience Genetics, Eli Lilly and Company, Surrey, United Kingdom

38. Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, United Kingdom

39. School of Life Sciences, University of Essex, Colchester, United Kingdom

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.

Funder

Medical Research Council

Karolinska Institutet

National Institutes of Health

National Institute of Mental Health

Finland Centre of Excellence in Complex Disease Genetics

Academy of Finland

Vetenskapsrådet

European Union 7th Framework Programme

NIHR

Netherlands Organisation for Scientific Research

Publisher