Study Report

Reference	Hashimoto, R.,2005(a) PMID: 15866548
Citation	Hashimoto, R., T. Okada, et al. (2005). The breakpoint cluster region gene on chromosome 22q11 is associated with bipolar disorder. Biol Psychiatry 57(10): 1097-1102.
Disease Type	Bipolar Disorder & Major Depressive Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	171 bipolar disorder patients(102 bipolar I and 69 bipolar II), 329 major depressive disorder patients and 351 healthy controls
SNP/Region/Marker Size	11 SNPs
Predominant Ethnicity	Mongloid
Population	Japanese
Gender	65 males and 106 females in BP cases,116 males and 213 females in MDD cases and 170 males and 181 females in controls
Age Group	Adults : mean age: 50.8 years [SD 14.9],39.2 years [SD 15.2](onset) in BP cases, 54.3 years [SD 16.0],46.7 years [SD 15.3](onset) in MDD cases and 40.2 years [SD 12.0] in controls

Sample Diagnosis	DSM
Sample Status	Subjects were 171 patients with bipolar disorder (102 bipolar I [43 males and 59 females] and 69 bipolar II patients [22 males and 47 females]),329 patients with major depressive disorder and 351 healthy controls.In addition, subjects who were examined in our previous study on the XBP1 gene (Kakiuchi et al 2003), were included in this study; 83 patients with bipolar disorder (27 males and 56 females with mean age of 48.1 years [SD 14.6] and mean age of onset of 35.9 years [SD 15.1], 57 bipolar I [23 males and 34 females] and 26 bipolar II patients [4 males and 22 females]) and 97 healthy controls (51 males and 46 females with mean age of 38.8 years[SD 13.4]). All the subjects were biologically unrelated Japanese.Consensus diagnosis was made for each patient by at least two trained psychiatrists according to the DSM-IV criteria, based on all available information, including clinical interview, medical records and other research assessments. Controls were healthy volunteers who had no current or past contact to psychiatric services. Subjects with significant medical problems, history of head trauma, neurosurgery and alcohol or substance abuse were excluded. After description of the study, written informed consent was obtained from every subject. The study protocol was approved by institutional ethical committees (Showa University School of Medicine, RIKEN Brain Science Institute and National Center of Neurology and Psychiatry, Tokyo, Japan).
Technique	genotyping
Statistical Method	Statistical analysis of association studies was performed using SNPAlyse software (DYNACOM, Yokohama, Japan). The presence of Hardy-Weinberg equilibrium was examined using the X2 test for goodness of fit. Allele distributions between patients and controls were analyzed by the X2 test for independence. The measures of linkage disequilibrium (LD), denoted as D' and r2,were calculated from the haplotype frequency using Expectation-Maximization algorithm.
Result Summary	RESULTS: Significant allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was a significant association with major depression in six SNPs. S796 allele carriers were in excess in bipolar II patients (p = .0046, odds ratio = 3.1, 95% CI 1.53-8.76). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). CONCLUSIONS: Our results suggest that genetic variations in the BCR gene could confer susceptibility to bipolar disorder and major depressive disorder.