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

Hannon, Eilis, Dempster, Emma L., Mansell, Georgina, Burrage, Joe, Bass, Nick, Bohlken, Marc M., Corvin, Aiden, Curtis, Charles J., Dempster, David, Di Forti, Marta, Dinan, Timothy G., Donohoe, Gary, Gaughran, Fiona, Gill, Michael, Gillespie, Amy, Gunasinghe, Cerisse, Hulshoff, Hilleke E., Hultman, Christina M., Johansson, Viktoria, Kahn, René S., Kaprio, Jaakko, Kenis, Gunter, Kowalec, Kaarina, MacCabe, James, McDonald, Colm, McQuillin, Andrew, Morris, Derek W., Murphy, Kieran C., Mustard, Colette J., Nenadic, Igor, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Quattrone, Diego, Richards, Alexander L., Rutten, Bart P.F., St. Clair, David, Therman, Sebastian, Toulopoulou, Timothea, Van Os, Jim, Waddington, John L., Sullivan, Patrick, Vassos, Evangelos, Breen, Gerome, Collier, David A., Murray, Robin M., Schalwyk, Leo and Mill, Jonathan 2021. DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia. eLife 10 , e58430. 10.7554/eLife.58430

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This article is distributed under the terms of the Creative Commons Attribution License
Publisher:	eLife Sciences Publications
ISSN:	2050-084X
Date of First Compliant Deposit:	5 March 2021
Date of Acceptance:	23 February 2021
Last Modified:	11 May 2023 05:53
URI:	https://orca.cardiff.ac.uk/id/eprint/139338

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