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

  1. Eilis Hannon
  2. Emma L Dempster
  3. Georgina Mansell
  4. Joe Burrage
  5. Nick Bass
  6. Marc M Bohlken
  7. Aiden Corvin
  8. Charles J Curtis
  9. David Dempster
  10. Marta Di Forti
  11. Timothy G Dinan
  12. Gary Donohoe
  13. Fiona Gaughran
  14. Michael Gill
  15. Amy Gillespie
  16. Cerisse Gunasinghe
  17. Hilleke E Hulshoff
  18. Christina M Hultman
  19. Viktoria Johansson
  20. René S Kahn
  21. Jaakko Kaprio
  22. Gunter Kenis
  23. Kaarina Kowalec
  24. James MacCabe
  25. Colm McDonald
  26. Andrew McQuillin
  27. Derek W Morris
  28. Kieran C Murphy
  29. Colette J Mustard
  30. Igor Nenadic
  31. Michael C O'Donovan
  32. Diego Quattrone
  33. Alexander L Richards
  34. Bart PF Rutten
  35. David St. Clair
  36. Sebastian Therman
  37. Timothea Toulopoulou
  38. Jim Van Os
  39. John L Waddington
  40. Wellcome Trust Case Control Consortium 2
  41. CRESTAR consortium
  42. Patrick Sullivan
  43. Evangelos Vassos
  44. Gerome Breen
  45. David A Collier
  46. Robin M Murray
  47. Leo Schalwyk
  48. Jonathan Mill  Is a corresponding author
  1. University of Exeter, United Kingdom
  2. University College London, United Kingdom
  3. University Medical Center Utrecht, Netherlands
  4. Trinity College Dublin, Ireland
  5. King's College London, United Kingdom
  6. University College Cork, Ireland
  7. National University of Ireland Galway, Ireland
  8. University of Oxford, United Kingdom
  9. Karolinska Institutet, Sweden
  10. Icahn School of Medicine at Mount Sinai, United States
  11. University of Helsinki/FIMM, Finland
  12. Maastricht University, Netherlands
  13. Royal College of Surgeons in Ireland, Ireland
  14. University of the Highlands and Islands, United Kingdom
  15. Jena University Hospital, Germany
  16. Cardiff University, United Kingdom
  17. Maastricht University Medical Centre, Netherlands
  18. University of Aberdeen, United Kingdom
  19. Finnish Institute for Health and Welfare, Finland
  20. Bilkent University, Turkey
  21. University of North Carolina at Chapel Hill, United States
  22. Eli Lilly and Company, United Kingdom
  23. University of Essex, United Kingdom

Abstract

We performed a systematic analysis of blood DNA methylation profiles from 4,483 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 1,048 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.

Data availability

Raw and processed data for the UCL, Aberdeen and Dublin cohorts are available through GEO accession numbers GSE84727, GSE80417, and GSE147221 respectively.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Eilis Hannon

    Complex Disease Epigenetics Group, University of Exeter, Exeter, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6840-072X
  2. Emma L Dempster

    College of Medicine and Health, University of Exeter, Exeter, United Kingdom
    Competing interests
    No competing interests declared.
  3. Georgina Mansell

    College of Medicine and Health, University of Exeter, Exeter, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2620-1786
  4. Joe Burrage

    College of Medicine and Health, University of Exeter, Exeter, United Kingdom
    Competing interests
    No competing interests declared.
  5. Nick Bass

    Division of Psychiatry, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Marc M Bohlken

    Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  7. Aiden Corvin

    Department of Psychiatry and Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland
    Competing interests
    No competing interests declared.
  8. Charles J Curtis

    Social, Genetic & Developmental Psychiatry Centre, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  9. David Dempster

    Social, Genetic & Developmental Psychiatry Centre, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  10. Marta Di Forti

    Social, Genetic & Developmental Psychiatry Centre, King's College London, London, United Kingdom
    Competing interests
    Marta Di Forti, M Di Forti reports personal fees from Janssen, outside the submitted work..
  11. Timothy G Dinan

    APC Microbiome Institute, University College Cork, Cork, Ireland
    Competing interests
    No competing interests declared.
  12. Gary Donohoe

    Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Dublin, Ireland
    Competing interests
    No competing interests declared.
  13. Fiona Gaughran

    Psychosis Studies, King's College London, London, United Kingdom
    Competing interests
    Fiona Gaughran, FG has received honoraria from Lundbeck, Otsuka, and Sunovion, She has a family member with professional links to Lilly and GSK, including shares..
  14. Michael Gill

    Centre for Neuroimaging and Cognitive Genomics (NICOG), Trinity College Dublin, Dublin, Ireland
    Competing interests
    No competing interests declared.
  15. Amy Gillespie

    Department of Psychiatry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  16. Cerisse Gunasinghe

    Psychosis Studies, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  17. Hilleke E Hulshoff

    Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  18. Christina M Hultman

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  19. Viktoria Johansson

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  20. René S Kahn

    Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  21. Jaakko Kaprio

    Department of Public Health, University of Helsinki/FIMM, Helsinki, Finland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3716-2455
  22. Gunter Kenis

    Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, Netherlands
    Competing interests
    No competing interests declared.
  23. Kaarina Kowalec

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Competing interests
    Kaarina Kowalec, Kaarina Kowalec has consulted with Emerald Lake Safety Ltd. (2017-2018) and has received speaker honoraria from Biogen/Fraser Health Multiple Sclerosis Clinic (2018). Both are unrelated to the current work in submission..
  24. James MacCabe

    Social, Genetic & Developmental Psychiatry Centre, King's College London, London, United Kingdom
    Competing interests
    James MacCabe, James MacCabe has received research funding from H Lundbeck .
  25. Colm McDonald

    Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Galway, Ireland
    Competing interests
    No competing interests declared.
  26. Andrew McQuillin

    Division of Psychiatry, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1567-2240
  27. Derek W Morris

    Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Galway, Ireland
    Competing interests
    No competing interests declared.
  28. Kieran C Murphy

    Department of Psychiatry, Royal College of Surgeons in Ireland, Dubin, Ireland
    Competing interests
    No competing interests declared.
  29. Colette J Mustard

    Division of Biomedical Sciences, University of the Highlands and Islands, Inverness, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5834-2765
  30. Igor Nenadic

    Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany
    Competing interests
    No competing interests declared.
  31. Michael C O'Donovan

    MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    Michael C O'Donovan, MOD is supported by a collaborative research grant from Takeda Pharmaceuticals. Takeda played no part in the conception, design, implementation, or interpretation of this study.   .
  32. Diego Quattrone

    Social, Genetic & Developmental Psychiatry Centre, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  33. Alexander L Richards

    MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
    Competing interests
    No competing interests declared.
  34. Bart PF Rutten

    Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9834-6346
  35. David St. Clair

    The Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
    Competing interests
    No competing interests declared.
  36. Sebastian Therman

    Department of Public Health Solutions, Mental Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9407-4905
  37. Timothea Toulopoulou

    Aysel Sabuncu Brain Research Centre (ASBAM), Bilkent University, Ankara, Turkey
    Competing interests
    No competing interests declared.
  38. Jim Van Os

    Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  39. John L Waddington

    Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland
    Competing interests
    No competing interests declared.
  40. Wellcome Trust Case Control Consortium 2

  41. CRESTAR consortium

  42. Patrick Sullivan

    Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    Patrick Sullivan, PF Sullivan reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient). Past three years: Pfizer (scientific advisory board)..
  43. Evangelos Vassos

    Psychosis Studies, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  44. Gerome Breen

    Social, Genetic & Developmental Psychiatry Centre, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  45. David A Collier

    Eli Lilly and Company, Windlesham, United Kingdom
    Competing interests
    David A Collier, David A Collier is a full time employee and stockholder of Eli Lilly and Company..
  46. Robin M Murray

    Department of Psychosis Studies, King's College London, London, United Kingdom
    Competing interests
    Robin M Murray, reports personal fees from Janssen, Lundbeck, Sunovion, Recordati and Otsuka.
  47. Leo Schalwyk

    University of Essex, Colchester, United Kingdom
    Competing interests
    No competing interests declared.
  48. Jonathan Mill

    University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
    For correspondence
    j.mill@exeter.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1115-3224

Funding

Medical Research Council (MR/K013807/1)

  • Jonathan Mill

Medical Research Council (MR/R005176/1)

  • Jonathan Mill

Medical Research Council (MR/M008924/1)

  • Jonathan Mill

Karolinska Institutet (ALF 20090183)

  • Christina M Hultman

Karolinska Institutet (ALF 20100305)

  • Christina M Hultman

National Institutes of Health (R01 MH52857)

  • Christina M Hultman

National Institute of Mental Health (R01MH077139)

  • Patrick Sullivan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Margaret M McCarthy, University of Maryland School of Medicine, United States

Publication history

  1. Received: May 1, 2020
  2. Accepted: February 23, 2021
  3. Accepted Manuscript published: February 26, 2021 (version 1)
  4. Version of Record published: March 29, 2021 (version 2)

Copyright

© 2021, Hannon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Eilis Hannon
  2. Emma L Dempster
  3. Georgina Mansell
  4. Joe Burrage
  5. Nick Bass
  6. Marc M Bohlken
  7. Aiden Corvin
  8. Charles J Curtis
  9. David Dempster
  10. Marta Di Forti
  11. Timothy G Dinan
  12. Gary Donohoe
  13. Fiona Gaughran
  14. Michael Gill
  15. Amy Gillespie
  16. Cerisse Gunasinghe
  17. Hilleke E Hulshoff
  18. Christina M Hultman
  19. Viktoria Johansson
  20. René S Kahn
  21. Jaakko Kaprio
  22. Gunter Kenis
  23. Kaarina Kowalec
  24. James MacCabe
  25. Colm McDonald
  26. Andrew McQuillin
  27. Derek W Morris
  28. Kieran C Murphy
  29. Colette J Mustard
  30. Igor Nenadic
  31. Michael C O'Donovan
  32. Diego Quattrone
  33. Alexander L Richards
  34. Bart PF Rutten
  35. David St. Clair
  36. Sebastian Therman
  37. Timothea Toulopoulou
  38. Jim Van Os
  39. John L Waddington
  40. Wellcome Trust Case Control Consortium 2
  41. CRESTAR consortium
  42. Patrick Sullivan
  43. Evangelos Vassos
  44. Gerome Breen
  45. David A Collier
  46. Robin M Murray
  47. Leo Schalwyk
  48. Jonathan Mill
(2021)
DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
eLife 10:e58430.
https://doi.org/10.7554/eLife.58430

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