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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.

Original publication

DOI

10.1073/pnas.0800643105

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

30/09/2008

Volume

105

Pages

14940 - 14945

Keywords

3' Untranslated Regions, Alleles, Amino Acid Sequence, Bipolar Disorder, Haplotypes, Heterozygote, Humans, INDEL Mutation, Molecular Sequence Data, Nucleic Acid Conformation, Polymorphism, Single Nucleotide, Receptors, Kainic Acid, Sequence Deletion, Transcription, Genetic