Transcriptome sequencing of the anterior cingulate in bipolar disorder: dysregulation of G protein-coupled receptors

Am J Psychiatry. 2015 Nov 1;172(11):1131-40. doi: 10.1176/appi.ajp.2015.14101279. Epub 2015 Aug 4.


Objective: Gene expression dysregulation in the brain has been associated with bipolar disorder through candidate gene and microarray expression studies, but questions remain about isoform-specific dysregulation and the role of noncoding RNAs whose importance in the brain has been suggested recently but not yet characterized for bipolar disorder.

Method: The authors used RNA sequencing, a powerful technique that captures the complexity of gene expression, in postmortem tissue from the anterior cingulate cortex from 13 bipolar disorder case subjects and 13 matched comparison subjects. Differential expression was computed, and a global pattern of downregulation was detected, with 10 transcripts significant at a false discovery rate ≤5%. Importantly, all 10 genes were also replicated in an independent RNA sequencing data set (N=61) from the anterior cingulate cortex.

Results: Among the most significant results were genes coding for class A G protein-coupled receptors: SSTR2 (somatostatin receptor 2), CHRM2 (cholinergic receptor, muscarinic 2), and RXFP1 (relaxin/insulin-like family peptide receptor 1). A gene ontology analysis of the entire set of differentially expressed genes pointed to an overrepresentation of genes involved in G protein-coupled receptor regulation. The top genes were followed up by querying the effect of treatment with mood stabilizers commonly prescribed in bipolar disorder, which showed that these drugs modulate expression of the candidate genes.

Conclusions: By using RNA sequencing in the postmortem bipolar disorder brain, an interesting profile of G protein-coupled receptor dysregulation was identified, several new bipolar disorder genes were indicated, and the noncoding transcriptome in bipolar disorder was characterized. These findings have important implications with regard to fine-tuning our understanding of the bipolar disorder brain, as well as for identifying potential new drug target pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antimanic Agents / pharmacology
  • Bipolar Disorder / genetics*
  • Bipolar Disorder / metabolism
  • Carbamazepine / pharmacology
  • Case-Control Studies
  • Cell Line
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Gyrus Cinguli / metabolism*
  • Humans
  • In Vitro Techniques
  • Lithium Compounds / pharmacology
  • Male
  • Middle Aged
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Receptor, Muscarinic M2 / drug effects
  • Receptor, Muscarinic M2 / genetics*
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, Peptide / drug effects
  • Receptors, Peptide / genetics*
  • Receptors, Somatostatin / drug effects
  • Receptors, Somatostatin / genetics*
  • Sequence Analysis, RNA
  • Valproic Acid / pharmacology


  • Antimanic Agents
  • CHRM2 protein, human
  • Lithium Compounds
  • RNA, Messenger
  • RXFP1 protein, human
  • Receptor, Muscarinic M2
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Receptors, Somatostatin
  • SSTR2 protein, human
  • Carbamazepine
  • Valproic Acid