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.
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.
Metrics
-
- 5,898
- views
-
- 580
- downloads
-
- 81
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Genetics and Genomics
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
-
- Genetics and Genomics
Endocrine disrupting chemicals (EDCs) such as bisphenol S (BPS) are xenobiotic compounds that can disrupt endocrine signaling due to steric similarities to endogenous hormones. EDCs have been shown to induce disruptions in normal epigenetic programming (epimutations) and differentially expressed genes (DEGs) that predispose disease states. Most interestingly, the prevalence of epimutations following exposure to many EDCs persists over multiple generations. Many studies have described direct and prolonged effects of EDC exposure in animal models, but many questions remain about molecular mechanisms by which EDC-induced epimutations are introduced or subsequently propagated, whether there are cell type-specific susceptibilities to the same EDC, and whether this correlates with differential expression of relevant hormone receptors. We exposed cultured pluripotent (iPS), somatic (Sertoli and granulosa), and primordial germ cell-like (PGCLC) cells to BPS and found that differential incidences of BPS-induced epimutations and DEGs correlated with differential expression of relevant hormone receptors inducing epimutations near relevant hormone response elements in somatic and pluripotent, but not germ cell types. Most interestingly, we found that when iPS cells were exposed to BPS and then induced to differentiate into PGCLCs, the prevalence of epimutations and DEGs was largely retained, however, >90% of the specific epimutations and DEGs were replaced by novel epimutations and DEGs. These results suggest a unique mechanism by which an EDC-induced epimutated state may be propagated transgenerationally.
