DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
- University of Exeter, United Kingdom
- University College London, United Kingdom
- University Medical Center Utrecht, Netherlands
- Trinity College Dublin, Ireland
- King's College London, United Kingdom
- University College Cork, Ireland
- National University of Ireland Galway, Ireland
- University of Oxford, United Kingdom
- Karolinska Institutet, Sweden
- Icahn School of Medicine at Mount Sinai, United States
- University of Helsinki/FIMM, Finland
- Maastricht University, Netherlands
- Royal College of Surgeons in Ireland, Ireland
- University of the Highlands and Islands, United Kingdom
- Jena University Hospital, Germany
- Cardiff University, United Kingdom
- Maastricht University Medical Centre, Netherlands
- University of Aberdeen, United Kingdom
- Finnish Institute for Health and Welfare, Finland
- Bilkent University, Turkey
- University of North Carolina at Chapel Hill, United States
- Eli Lilly and Company, United Kingdom
- 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.
Article and author information
Author details
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
- Margaret M McCarthy, University of Maryland School of Medicine, United States
Publication history
- Received: May 1, 2020
- Accepted: February 23, 2021
- Accepted Manuscript published: February 26, 2021 (version 1)
- 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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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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