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Cited by 101Schizophrenia research and treatmentEpigenetics and DNA MethylationBipolar Disorder and Treatment

Circuit- and Diagnosis-Specific DNA Methylation Changes at γ-Aminobutyric Acid–Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder

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Ruzicka, W. Brad, Subburaju, Sivan, Benes, Francine M.·2015·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2015.49PMC PMC5547581
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Abstract

IMPORTANCE: Dysfunction related to γ-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression. Several genes within this GAD1 regulatory network show diagnosis- and sector-specific expression changes within the circuitry of the hippocampus, influencing abnormal GAD1 expression in schizophrenia and bipolar disorder. OBJECTIVE: To investigate the hypothesis that aberrant DNA methylation contributes to circuit- and diagnosis-specific abnormal expression of GAD1 regulatory network genes in psychotic illness. DESIGN, SETTING, AND PARTICIPANTS: This epigenetic association study targeting GAD1 regulatory network genes was conducted between July 1, 2012, and June 30, 2014. Postmortem human hippocampus tissue samples were obtained from 8 patients with schizophrenia, 8 patients with bipolar disorder, and 8 healthy control participants matched for age, sex, postmortem interval, and other potential confounds from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, Massachusetts. We extracted DNA from laser-microdissected stratum oriens tissue of cornu ammonis 2/3 (CA2/3) and CA1 postmortem human hippocampus, bisulfite modified it, and assessed it with the Infinium HumanMethylation450 BeadChip (Illumina, Inc). The subset of CpG loci associated with GAD1 regulatory network genes was analyzed in R version 3.1.0 software (R Foundation) using the minfi package. Findings were validated using bisulfite pyrosequencing. MAIN OUTCOMES AND MEASURES: Methylation levels at 1308 GAD1 regulatory network-associated CpG loci were assessed both as individual sites to identify differentially methylated positions and by sharing information among colocalized probes to identify differentially methylated regions. RESULTS: A total of 146 differentially methylated positions with a false detection rate lower than 0.05 were identified across all 6 groups (2 circuit locations in each of 3 diagnostic categories), and 54 differentially methylated regions with P < .01 were identified in single-group comparisons. Methylation changes were enriched in MSX1, CCND2, and DAXX at specific loci within the hippocampus of patients with schizophrenia and bipolar disorder. CONCLUSIONS AND RELEVANCE: This work demonstrates diagnosis- and circuit-specific DNA methylation changes at a subset of GAD1 regulatory network genes in the human hippocampus in schizophrenia and bipolar disorder. These genes participate in chromatin regulation and cell cycle control, supporting the concept that the established GABAergic dysfunction in these disorders is related to disruption of GABAergic interneuron physiology at specific circuit locations within the human hippocampus.

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  • A dysregulation of multiple DNAm positions in the regulatory network of GAD1 was identified in patients with SCZ and BD compared to controls.

    “A dysregulation of multiple DNAm positions in the regulatory network of GAD1, was identified in patients with SCZ and BD compared to controls (Ruzicka, Subburaju, & Benes, 2015).”

    From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Ruzicka, Subburaju, & Benes, 2015

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Cited by

Sorted by citations

Authors
Ruzicka, W. B., Subburaju, S., & Benes, F. M.
Affiliations
Harvard University (US)
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2015-06-01
Volume
72
Issue
6
Pages
541
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2015.49
PMC
PMC5547581
OpenAlex
W2104031918
Cited by
101
References
3
Citations by year
2026: 3 · 2025: 2 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 13 · 2019: 8 · 2018: 12 · 2017: 13 · 2016: 18 · 2015: 5
FWCI
13.00
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (MH077175, R25MH094612, MH/NS077550, R34MH077550, R01MH077175)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords
DNA methylation, GABAergic neurotransmission, GAD1, schizophrenia, bipolar disorder, CA2/3, CA1, differentially methylated regions, differentially methylated positions, epigenetics, psychosis, GABAA receptor subunits, GABA-A receptor alpha1 subunit
MeSH terms
Bipolar Disorder, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Hippocampus, Humans, Nuclear Proteins, Schizophrenia, Signal Transduction, Case-Control Studies, Molecular Chaperones, CpG Islands, DNA Methylation, Adaptor Proteins, Signal Transducing, MSX1 Transcription Factor, Genetic Association Studies, Cyclin D2, Co-Repressor Proteins

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