Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers 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 Forta
  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. Rene S Kahn
  21. Jaakko Kaprio
  22. Gunter Kenis
  23. Kaarina Kowalec
  24. James MacCabe
  25. Colm McDonald
  26. Andew McQuillin
  27. Derek W Morris
  28. Kieran C Murphy
  29. Collette 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. CREeTable AR consortium
  42. Patrick Sullivan
  43. Evangelos Vassos
  44. Gerome Breen
  45. David Andrew Collier
  46. Robin Murray
  47. Leonard S Schalkwyk
  48. Jonathan Mill
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Abstract

Objective

Psychosis - a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions - is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm associated with psychosis, schizophrenia, and treatment-resistant schizophrenia, also exploring measures of biological ageing, smoking, and blood cell composition derived from DNAm data to identify molecular biomarkers of disease.

Methods

We quantified DNAm across the genome in blood samples from 4,483 participants from seven case-control cohorts including patients with schizophrenia or first-episode psychosis. Measures of biological age, cellular composition and smoking status were derived from DNAm data using established algorithms. DNAm and derived measures were analyzed within each cohort and the results combined by meta-analysis.

Results

Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNAm data, with the largest differences seen in treatment-resistant schizophrenia patients. DNAm at 95 CpG sites was significantly different between psychosis cases and controls, with 1,048 differentially methylated positions (DMPs) identified between schizophrenia cases and controls. Schizophrenia-associated DMPs colocalize to regions identified in genetic association studies, with genes annotated to these sites enriched for pathways relevant to disease. Finally, a number of the schizophrenia associated differences were only present in the treatment-resistant schizophrenia subgroup.

Conclusions

We show that DNAm data can be leveraged to derive measures of blood cell counts and smoking that are strongly associated with psychosis. Our DNAm meta-analysis identified multiple DMPs associated with both psychosis and a more refined diagnosis of schizophrenia, with evidence for differential methylation associated with treatment-resistant schizophrenia that potentially reflects exposure to clozapine.

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