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, Rene S. KahnJaakko Kaprio, Gunter Kenis, Kaarina Kowalec, James Maccabe, Colm McDonald, Andew McQuillin, Derek W. Morris, Kieran C. Murphy, Collette Mustard, Igor Nenadic, Michael C. O'donovan, Diego Quattrone, Alexander L. Richards, Bart P.F. Rutten, David St Clair, Sebastian Therman, Timothea Toulopoulou, Jim Van Os, John L. Waddington, Wellcome Trust Case Control Consortium 2, CRESTAR consortium, Patrick Sullivan, Evangelos Vassos, Gerome Breen, David Andrew Collier, Robin Murray, Leonard S. Schalkwyk, Jonathan Mill*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere58430
Number of pages31
JournaleLife
Volume10
Early online date26 Feb 2021
DOIs
Publication statusPublished - 26 Feb 2021

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