Glutamate receptor gene variant linked to bipolar disorder
medwireNews: Researchers have found an association between a glutamate receptor 3 gene (GRM3) variant and bipolar disorder which, if confirmed, could provide a potential marker for personalized treatment of the psychiatric condition.
They report that the base pair variant rs148754219, which was found in the Kozak sequence of exon 1 of the GRM3 gene, was significantly over-represented in their sample of 1099 patients with bipolar disorder, at an odds ratio above 4, compared with 1152 mentally healthy controls.
This is "suggestive of moderate risk for bipolar disorder," say Hugh Gurling (University College London, UK) and colleagues.
Indeed, 19 (1.7%) of the bipolar patients were heterozygous for the variant, compared with just four (0.3%) of the controls.
"To our knowledge, this is the first study that reports a possible, although unconfirmed, rare and functional base pair change that is significantly associated with bipolar disorder," Gurling et al write in JAMA Psychiatry.
Bioinformatic analysis indicated that the mutant allele of rs148754219 is likely to bind several more transcription factors than does the wild-type allele. This suggests that "this variant creates a transcription factor binding site likely to change GRM3 mRNA [messenger RNA] expression compared with the wild-type sequence," the researchers explain.
Their electrophoretic mobility shift assays showed evidence of this, in that the variant sequence caused protein/DNA band shifts compared with the wild-type sequence.
Luciferase gene assays also showed that the variant rs148754219 sequence influenced the translation efficiency of GRM3, causing total suppression of luciferase expression in two cell lines.
The researchers note that the variant is likely to affect gene expression at the posttranscriptional/translational levels, because mRNA levels for the mutant and wild-type alleles remained consistent.
They comment on the success of class II metabotropic glutamate receptor 3 drugs in treating anxiety and stress-related disorders and suggest that their GRM3 variant could be a potential biomarker for the use of such treatment in some bipolar patients.
"The finding needs confirmation in additional samples of unipolar and bipolar affective disorder as well as in alcoholism, where unipolar affective disorder is known to be a primary etiologic factor," the team adds.
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By Lucy Piper, Senior medwireNews Reporter