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Evidence that a single nucleotide polymorphism in the promoter of the g protein receptor kinase 3 gene is associated with bipolar disorder

Academic Article
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Overview

authors

  • Barrett, T. B.
  • Hauger, R. L.
  • Kennedy, J. L.
  • Sadovnick, A. D.
  • Remick, R. A.
  • Keck, P. E.
  • McElroy, S. L.
  • Alexander, M.
  • Shaw, S. H.
  • Kelsoe, J. R.

publication date

  • 2003

journal

  • Molecular Psychiatry  Journal

abstract

  • In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

subject areas

  • Animals
  • Base Sequence
  • Bipolar Disorder
  • Chromosomes, Human, Pair 22
  • G-Protein-Coupled Receptor Kinase 3
  • Genome, Human
  • Humans
  • Linkage Disequilibrium
  • Mice
  • Molecular Sequence Data
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases
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Research

keywords

  • G protein receptor kinases
  • SNP
  • bipolar disorder
  • chromosome 22
  • depression
  • genetic association
  • linkage disequilibrium
  • mania
  • receptor desensitization
  • transmission disequilibrium test
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Identity

International Standard Serial Number (ISSN)

  • 1359-4184

Digital Object Identifier (DOI)

  • 10.1038/sj.mp.4001268

PubMed ID

  • 12808434
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Additional Document Info

start page

  • 546

end page

  • 557

volume

  • 8

issue

  • 5

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