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- Title
Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder.
- Authors
Kandaswamy, Radhika; McQuillin, Andrew; Sharp, Sally I.; Fiorentino, Alessia; Anjorin, Adebayo; Blizard, Robert A.; Curtis, David; Gurling, Hugh M. D.
- Abstract
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 DN A 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 1 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 (rsl48754219) 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.
- Subjects
BIPOLAR disorder; THERAPEUTICS; GENETIC mutation; GENETIC testing; NUCLEOTIDE sequence; GLUTAMATE receptors; GENETIC markers; ALLELES
- Publication
JAMA Psychiatry, 2013, Vol 70, Issue 6, p591
- ISSN
2168-622X
- Publication type
Article
- DOI
10.1001/jamapsychiatry.2013.38