title: DNA methylation and expression of KCNQ3 in bipolar disorder.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kaminsky
authors.forename: Ilenna
authors.initials: I
authors.lastname: Jones
authors.forename: Ranjana
authors.initials: R
authors.lastname: Verma
authors.forename: Lena
authors.initials: L
authors.lastname: Saleh
authors.forename: Hersh
authors.initials: H
authors.lastname: Trivedi
authors.forename: Jerry
authors.initials: J
authors.lastname: Guintivano
authors.forename: Ryan
authors.initials: R
authors.lastname: Akman
authors.forename: Peter
authors.initials: P
authors.lastname: Zandi
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lee
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000187:drug effects / Q000235:genetics*; D051659:KCNQ3 Potassium Channel / Q000187:drug effects / Q000235:genetics*; D018020:Lithium Compounds / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D018692:Antimanic Agents; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; C496915:Kcnq2 protein, rat; C496918:Kcnq3 protein, rat; D018020:Lithium Compounds; D012333:RNA, Messenger; D014635:Valproic Acid
keywords: DNA methylation; KCNQ3; bipolar disorder; epigenetics; glia; neurons; pyrosequencing