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Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14940-5. doi: 10.1073/pnas.0800643105. Epub 2008 Sep 29.

A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder.

Author information

1
Medical Genetics, School of Clinical and Molecular Medicine, Molecular Medicine Centre, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom. ben.pickard@ed.ac.uk

Abstract

Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3' end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3' untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.

PMID:
18824690
PMCID:
PMC2567472
DOI:
10.1073/pnas.0800643105
[Indexed for MEDLINE]
Free PMC Article
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