Promoter variant in the GRK3 gene associated with bipolar disorder alters gene expression

Biol Psychiatry. 2008 Jul 15;64(2):104-10. doi: 10.1016/j.biopsych.2007.12.017. Epub 2008 Mar 21.


Background: We have previously reported a single nucleotide polymorphism (P-5, G-384A) in the proximal promoter of the gene for G protein receptor kinase 3 (GRK3) that was associated with bipolar disorder in two independent samples. In this study, we examined whether the G-384A variant has a functional effect on GRK3 transcription.

Methods: Electrophoretic mobility shift assays were conducted using nuclear extracts from both Hela cells and adult mouse cortex. Transcriptional function was also examined using a dual luciferase reporter system transfected into in vitro human neuroblastoma cells and cultured mouse cortical neurons.

Results: The G-384A variant abolished or reduced the formation of DNA-protein complexes using nuclear extract from both HeLa cells and adult mouse cortical neuron cells. However, gene expression was significantly enhanced by G-384A in both in vitro human neuroblastoma cells and cultured mouse cortical neurons.

Conclusions: These data suggest that the G-384A SNP in the promoter of human GRK3 gene represents an important functional variant. The G-384A variant may alter binding of Sp1/Sp4 transcription factors resulting in an increase in gene transcription and an increase in vulnerability to bipolar disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles*
  • Animals
  • Bipolar Disorder / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cerebral Cortex / pathology
  • Electrophoretic Mobility Shift Assay
  • G-Protein-Coupled Receptor Kinase 3 / genetics*
  • Gene Expression / genetics*
  • Gene Expression Regulation / genetics
  • Genetic Variation / genetics*
  • HeLa Cells
  • Humans
  • Mice
  • Neurons / pathology
  • Polymorphism, Single Nucleotide / genetics*
  • Promoter Regions, Genetic / genetics*
  • Sp1 Transcription Factor / genetics
  • Sp4 Transcription Factor / genetics
  • Transcription, Genetic / genetics


  • SP4 protein, human
  • Sp1 Transcription Factor
  • Sp4 Transcription Factor
  • G-Protein-Coupled Receptor Kinase 3
  • GRK3 protein, human