Study Report

Reference	Tsunoka, T.,2009 PMID: 19386277
Citation	Tsunoka, T., T. Kishi, et al. (2009). Association analysis of group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population. Prog Neuropsychopharmacol Biol Psychiatry 33(5): 875-879.
Disease Type	Bipolar Disorder & Major Depressive Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	325 MDD patients, 155 BP patients(96 patients with bipolar I disorder and 59 patients with bipolar II disorder) and 802 controls
SNP/Region/Marker Size	4 SNPs
Predominant Ethnicity	Mongloid
Population	Japanese
Gender	MDD patients:159 males and 166 females;BP patients:80 males and 75 females;healthy controls:351 males and 451 females
Age Group	Adults : Mean age(SD)(year):47.3(14.9) for MDD patients,47.9(14.2) for BP patients,37.2(15.9) for healthy controls

Sample Diagnosis	DSM
Sample Status	The subjects in the association analysis were 325 MDD patients(159 males and 166 females; mean age(standard deviation) 47.3(14.9years)), 155 BP patients (80 males and 75 females; 96 patients with bipolar I disorder and 59 patients with bipolar II disorder; 47.9(14.2 years)) and 802 healthy controls (351 males and 451 females;37.2(15.9 years)).Of the 325 MDD patients, 117 (58 males and 59 females; 44.8(16.7 years)) were treated with fluvoxamine and diagnosed according to DSM-IV criteriawith the consensus of at least two experienced psychiatrists on the basis of a review of medical records and assessments with the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). The remaining MDD patients were diagnosed according to DSM-IV criteria with the consensus of at least two experienced psychiatrists on the basis of unstructured interviews and a review ofmedical records. All subjects were unrelated to each other, ethnically Japanese, and lived in the central area of Japan. All healthy controls were also psychiatrically screened based on unstructured interviews. None had severe medical complications such as liver cirrhosis, renal failure, heart failure, or other Axis-I disorders according to DSM-IV.
Technique	genotyping
Statistical Method	Genotype deviation from the Hardy-Weinberg equilibrium (HWE)was evaluated by chi-square test (SAS/Genetics, release 8.2, SAS Japan Inc, Tokyo, Japan).Marker-trait association analysis was used to evaluate allele- and genotype-wise associations with the chi-square test (SAS/Genetics,release 8.2, SAS Japan Inc, Tokyo, Japan), and haplotype-wise association analysis was done with a likelihood ratio test using the COCAPHASE 2.403 program (Dudbridge, 2003). Bonferroni's correction was used to control inflation of the type I error rate. Power calculation was performed using a statistical program prepared by Purcell et al. (2003).
Result Summary	RESULTS: We found an association between rs6465084 in GRM3 and MDD in the allele-wise analysis after Bonferroni's correction (P-value=0.0371). However, we did not find any association between GRM3 and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analysis. We also did not detect any association between GRM2 and MDD, BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise or haplotype-wise analysis. DISCUSSION: We detected an association between only one marker (rs6465084) in GRM3 and Japanese MDD patients. However, because we did not perform an association analysis based on LD and a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.