BDgene

Core Gene from Gene Prioritization Pathways from PBA (Pathway-based Analysis) Enriched Pathways for Core Genes Enriched Pathways for Cross-disorder Genes

Search Gene with Disease Search Gene1 with Disease

Study Report

Comment on Study

View All Comments on Study

Basic Info

Reference	Kandaswamy R, 2013 PMID: 23575746
Citation	Kandaswamy, R., A. McQuillin, et al. (2013). "Genetic association, mutation screening, and functional analysis of a kozak sequence variant in the metabotropic glutamate receptor 3 gene in bipolar disorder." JAMA Psychiatry 70(6): 591-598.
Disease Type	bipolar disorder
Study Design	case-control
Study Type	Candidate-gene association study and Mutational study
Sample Size	1099 individuals with bipolar disorder, 1152 healthy controls
SNP/Region/Marker Size	3 SNPs
Predominant Ethnicity	Caucasian
Population	British or Irish

Detail Info

Sample Diagnosis	Research Diagnostic Criteria
Sample Status	This study included 1099 individuals with bipolar disorder, sampled in 2 cohorts. The first cohort (UCL1) comprised 506 bipolar I cases and 510 healthy comparison participants. The second cohort (UCL2) comprised 409 bipolar I (69%) and 184 bipolar II participants. Bipolar disorder diagnoses were confirmed in all bipolar participants according to Research Diagnostic Criteria. All of the bipolar participants were also rated with the 90- item Operational Criteria Checklist for Psychotic Disorders.
Technique	sequencing, genotyping, ELECTROPHORETIC MOBILITY SHIFT ASSAYS, CONSTRUCTION OF RECOMBINANT LUCIFERASE CONSTRUCTS, TRANSIENT TRANSFECTION AND LUCIFERASE ASSAYS, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION FOR MESSENGER RNA ANALYSIS
Statistical Method	Genotypic and allelic associations for SNPs were determined using X2 tests. Haplotype tests of association were performed using Haploview. Significance values shown for all analyses are uncorrected for multiple testing, and a cutoff significance value of P<0.05 was used.
Result Summary	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. 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.

SNPs reported by this study for BD (count: 3)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs2237563	GRM3	G/A		allelic P-value=3.85E-05, OR=1.56 for UCL1, P-value=0.95, OR=1.01 for UCL2, P-value=0.01, OR=1.22 for UCL1 and 2	It was found to be associated with bipolar affective disorde...... It was found to be associated with bipolar affective disorder in the UCL1 cohort in the GWA study. It showed no association with bipolar disorder in the UCL2 case-control sample. It remained significantly associated with bipolar disorder when we combined the genotyping data of the 3 SNPs in UCL1 and UCL2. More...	Positive
rs274621	GRM3	C/T		allelic P-value=0.007, OR=1.29 for UCL1, P-value=0.82, OR=0.98 for UCL2, P-value=0.18, OR=1.09 for UCL1 and 2	It was found to be associated with bipolar affective disorde...... It was found to be associated with bipolar affective disorder in the UCL1 cohort in the GWA study. It showed no association with bipolar disorder in the UCL2 case-control sample. It did not remain significantly associated with bipolar disorder when we combined the genotyping data of the 3 SNPs in UCL1 and UCL2. More...	Positive
rs2158786	GRM3	G/A		allelic P-value=0.01, OR=0.78 for UCL1, P-value=0.67, OR=0.96 for UCL2, P-value=0.03, OR=0.85 for UCL1 and 2	It was found to be associated with bipolar affective disorde...... It was found to be associated with bipolar affective disorder in the UCL1 cohort in the GWA study. It showed no association with bipolar disorder in the UCL2 case-control sample. It remained significantly associated with bipolar disorder when we combined the genotyping data of the 3 SNPs in UCL1 and UCL2. More...	Positive

Genes reported by this study for BD (count: 1)