DNA methylation and expression of KCNQ3 in bipolar disorder

Zachary A Kaminsky, Ilenna Jones, Ranjana Verma, Lena Saleh, Hersh Trivedi, Jerry Guintivano, Ryan Akman, Peter P Zandi, Richard Lee, James Bennett Potash

Research output: Contribution to journalArticle

Abstract

Objectives: Accumulating evidence implicates the potassium voltage-gated channel, KQT-like subfamily, member 2 and 3 (KCNQ2 and KCNQ3) genes in the etiology of bipolar disorder (BPD). Reduced KCNQ2 or KCNQ3 gene expression might lead to a loss of inhibitory M-current and an increase in neuronal hyperexcitability in disease. The goal of the present study was to evaluate epigenetic and gene expression associations of the KCNQ2 and KCNQ3 genes with BPD. Methods: DNA methylation and gene expression levels of alternative transcripts of KCNQ2 and KCNQ3 capable of binding the ankyrin G (ANK3) gene were evaluated using bisulfite pyrosequencing and the quantitative real-time polymerase chain reaction in the postmortem prefrontal cortex of subjects with BPD and matched controls from the McLean Hospital. Replication analyses of DNA methylation findings were performed using prefrontal cortical DNA obtained from the Stanley Medical Research Institute. Results: Significantly lower expression was observed in KCNQ3, but not KCNQ2. DNA methylation analysis of CpGs within an alternative exonic region of KCNQ3 exon 11 demonstrated significantly lower methylation in BPD, and correlated significantly with KCNQ3 mRNA levels. Lower KCNQ3 exon 11 DNA methylation was observed in the Stanley Medical Research Institute replication cohort, although only after correcting for mood stabilizer status. Mood stabilizer treatment in rats resulted in a slight DNA methylation increase at the syntenic KCNQ3 exon 11 region, which subsequent analyses suggested could be the result of alterations in neuronal proportion. Conclusion: The results of the present study suggest that epigenetic alterations in the KCNQ3 gene may be important in the etiopathogenesis of BPD and highlight the importance of controlling for medication and cellular composition-induced heterogeneity in psychiatric studies of the brain.

Original languageEnglish (US)
Pages (from-to)150-159
Number of pages10
JournalBipolar Disorders
Volume17
Issue number2
DOIs
StatePublished - Mar 1 2015

Fingerprint

DNA Methylation
Bipolar Disorder
Exons
Gene Expression
Epigenomics
Genes
Biomedical Research
Ankyrins
Voltage-Gated Potassium Channels
Prefrontal Cortex
Methylation
Psychiatry
Real-Time Polymerase Chain Reaction
Messenger RNA
DNA
Brain

Keywords

  • Bipolar disorder
  • DNA methylation
  • Epigenetics
  • Glia
  • KCNQ3
  • Neurons
  • Pyrosequencing

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Kaminsky, Z. A., Jones, I., Verma, R., Saleh, L., Trivedi, H., Guintivano, J., ... Potash, J. B. (2015). DNA methylation and expression of KCNQ3 in bipolar disorder. Bipolar Disorders, 17(2), 150-159. https://doi.org/10.1111/bdi.12230

DNA methylation and expression of KCNQ3 in bipolar disorder. / Kaminsky, Zachary A; Jones, Ilenna; Verma, Ranjana; Saleh, Lena; Trivedi, Hersh; Guintivano, Jerry; Akman, Ryan; Zandi, Peter P; Lee, Richard; Potash, James Bennett.

In: Bipolar Disorders, Vol. 17, No. 2, 01.03.2015, p. 150-159.

Research output: Contribution to journalArticle

Kaminsky, ZA, Jones, I, Verma, R, Saleh, L, Trivedi, H, Guintivano, J, Akman, R, Zandi, PP, Lee, R & Potash, JB 2015, 'DNA methylation and expression of KCNQ3 in bipolar disorder', Bipolar Disorders, vol. 17, no. 2, pp. 150-159. https://doi.org/10.1111/bdi.12230
Kaminsky ZA, Jones I, Verma R, Saleh L, Trivedi H, Guintivano J et al. DNA methylation and expression of KCNQ3 in bipolar disorder. Bipolar Disorders. 2015 Mar 1;17(2):150-159. https://doi.org/10.1111/bdi.12230
Kaminsky, Zachary A ; Jones, Ilenna ; Verma, Ranjana ; Saleh, Lena ; Trivedi, Hersh ; Guintivano, Jerry ; Akman, Ryan ; Zandi, Peter P ; Lee, Richard ; Potash, James Bennett. / DNA methylation and expression of KCNQ3 in bipolar disorder. In: Bipolar Disorders. 2015 ; Vol. 17, No. 2. pp. 150-159.
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