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Original Article |

Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder

Radhika Kandaswamy, MSc, MPhil, PhD; Andrew McQuillin, PhD; Sally I. Sharp, PhD; Alessia Fiorentino, PhD; Adebayo Anjorin, MBchB, MSc, MRCPsych; Robert A. Blizard, MSc, MSc; David Curtis, MBBS, MD, PhD, MRCPsych; Hugh M. D. Gurling, MBBS, MD, MPhil, FRCPsych
JAMA Psychiatry. 2013;70(6):591-598. doi:10.1001/jamapsychiatry.2013.38.
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Importance Genetic markers at the gene encoding the metabotropic glutamate receptor 3 (GRM3) showed allelic association with bipolar disorder.

Objective To screen the GRM3 gene and adjacent control regions of genomic DNA in volunteers with bipolar affective disorder for mutations increasing susceptibility to bipolar disorder.

Design Sequencing and high-resolution melting curve analysis of DNA followed by genotyping was carried out in 1099 patients with bipolar affective disorder and 1152 healthy comparator individuals.

Setting Participants with bipolar disorder were recruited from National Health Service psychiatric services and from patient organizations.

Participants Individuals were included if they had Research Diagnostic Criteria diagnoses of bipolar I and bipolar II disorder and were of British or Irish ancestry.

Main Outcomes and Measures Identification of base pair changes in the GRM3 gene that affected expression or function of the GRM3 receptor that also showed an allelic association with bipolar disorder.

Results A base pair variant (rs148754219) was found in the Kozak sequence of exon 1 of the GRM3 gene, 2 bases before the translation start codon of one of the receptor isoforms, in 23 of 2251 people who were screened and genotyped. Nineteen of the 1099 bipolar cases (1.7%) were mutation carriers compared with 4 of 1152 healthy comparators (0.3%). The variant was associated with bipolar disorder (P = .005; odds ratio, 4.20). Bioinformatic, electrophoretic mobility shift assay, and gene expression analysis found that the variant created a new transcription factor protein binding site and had a strong effect on gene transcription and translation.

Conclusions and Relevance Confirmation of these findings is needed before the Kozak sequence variant can be accepted as a potential marker for personalized treatment of affective disorders with drugs targeting the metabotropic glutamate receptor 3.

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Figure. Electrophoretic mobility shift assays performed with G (lanes 1-3) or A (lanes 4-15) allele probes and SH-SY5Y cell nuclear extract. The DNA-protein complex (band) formed with A allele was competed in a concentration-dependent manner by the unlabelled A allele (lanes 5-10) but not by the unlabelled G allele (lanes 11-15).

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