Methylome-Wide Association Study of Schizophrenia: Identifying Blood Biomarker Signatures of Environmental Insults
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IMPORTANCE: Epigenetic studies present unique opportunities to advance schizophrenia research because they can potentially account for many of its clinical features and suggest novel strategies to improve disease management. OBJECTIVE: To identify schizophrenia DNA methylation biomarkers in blood. DESIGN, SETTING, AND PARTICIPANTS: The sample consisted of 759 schizophrenia cases and 738 controls (N = 1497) collected in Sweden. We used methyl-CpG-binding domain protein-enriched genome sequencing of the methylated genomic fraction, followed by next-generation DNA sequencing. We obtained a mean (SD) number of 68 (26.8) million reads per sample. This massive data set was processed using a specifically designed data analysis pipeline. Critical top findings from our methylome-wide association study (MWAS) were replicated in independent case-control participants using targeted pyrosequencing of bisulfite-converted DNA. MAIN OUTCOMES AND MEASURES: Status of schizophrenia cases and controls. RESULTS: Our MWAS suggested a considerable number of effects, with 25 sites passing the highly conservative Bonferroni correction and 139 sites significant at a false discovery rate of 0.01. Our top MWAS finding, which was located in FAM63B, replicated with P = 2.3 × 10-10. It was part of the networks regulated by microRNA that can be linked to neuronal differentiation and dopaminergic gene expression. Many other top MWAS results could be linked to hypoxia and, to a lesser extent, infection, suggesting that a record of pathogenic events may be preserved in the methylome. Our findings also implicated a site in RELN, one of the most frequently studied candidates in methylation studies of schizophrenia. CONCLUSIONS AND RELEVANCE: To our knowledge, the present study is one of the first MWASs of disease with a large sample size using a technology that provides good coverage of methylation sites across the genome. Our results demonstrated one of the unique features of methylation studies that can capture signatures of environmental insults in peripheral tissues. Our MWAS suggested testable hypotheses about disease mechanisms and yielded biomarkers that can potentially be used to improve disease management.
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Self-citation
- Authors
- Aberg, K. A., McClay, J. L., Nerella, S., Clark, S., Kumar, G., Chen, W., Khachane, A. N., Xie, L., Hudson, A., Gao, G., Harada, A., Hultman, C. M., Sullivan, P. F., Magnusson, P. K. E., & van den Oord, E. J. C. G.
- Affiliations
- Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond
- Virginia Commonwealth University (US)
- Karolinska Institutet (SE)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2014-03-01
- Volume
- 71
- Issue
- 3
- Pages
- 255
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC4331014
- OpenAlex
- W2094005621
- Cited by
- 248
- References
- 78
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 11 · 2022: 11 · 2021: 14 · 2020: 17 · 2019: 15 · 2018: 39 · 2017: 27 · 2016: 40 · 2015: 32 · 2014: 25
- FWCI
- 16.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (K01AA021266)
- National Institute of Mental Health (R01MH077139, MH077139, RC2MH089996)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- schizophrenia, DNA methylation, methylome-wide association study, reelin, hypoxia, infection, neuronal differentiation, epigenetics
- MeSH terms
- Reelin Protein, Humans, Registries, Schizophrenia, Sweden, Biomarkers, Sequence Analysis, DNA, DNA Methylation, Genome-Wide Association Study, Epigenomics
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