BDgene

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

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Study Report

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Basic Info

Reference	Blair, I. P., 2006 PMID: 16402135
Citation	Blair, I. P., A. F. Chetcuti, et al. (2006). "Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele." Mol Psychiatry 11(4): 372-383.
Disease Type	Bipolar Disorder
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	Australian cohort: 65 bipolar pedigrees, 669 UK cases, 679 UK control individuals
SNP/Region/Marker Size	26 SNPs
Predominant Ethnicity	Caucasian
Population	British, Austrilian, Bulgarian
Gender	36% male in Australian cohort, 38% male in UK cases, 36% male in UK healthy controls, 43% males in UK trios and 46% males in Bulgarian trios
Age Group	adults : 98% were older than 40 years of age in Australian cohort, mean age 47 years (s.d.13 years) in UK cases, mean age 42 years (s.d.14 years) in UK controls, mean age 34.5 years in UK trios and mean age 31.9 years in Bulgarian trios

Detail Info

Sample Diagnosis	Diagnostic Interview for Genetic Studies (DIGS) and DSM-IV criteria
Sample Status	Australian: Cases were recruited as part of an ongoing bipolar genetics study via the Mood Disorders Unit, Prince of Wales Hospital/School of Psychiatry, University of New South Wales. A family history of psychiatric illness in first- or second-degree relative was present in 87% of cases. A lifetime psychotic episode was evident in 47% of cases. UK cases: These were recruited through mental health services in England and Wales with a mean age at the onset of illness 26 years (s.d. 10 years). A family history of psychiatric illness in first- or second-degree relative was present in 59% of cases. Seventy percent of UK bipolar cases had a lifetime occurrence of one or more psychotic features. UK and Bulgarian trios: A family history of psychiatric illness in first- or second-degree relative was present in 60% of UK trios, and 30% of Bulgarian trios. A lifetime occurrence of one or more psychotic features was present in 46% of UK trio cases, and 42% of Bulgarian trio cases.
Technique	Genotypes in the Australian cohort were determined by direct sequencing or by MALDI-TOF MS utilizing a Sequenom Autoflex Mass spectrometer. Genotypes in the UK and Bulgarian cohorts were determined using the AmplifluorTM method.
Statistical Method	For association analysis, the frequencies of alleles and genotypes observed in cases and controls were compared and tested by constructing contingency tables and performing chi-square analysis. Transmission disequilibrium was tested using the standard TDT test. For haplotype analysis, haplotype frequencies were estimated by the expectation-maximization algorithm implemented in the Arlequin program, and compared and tested by constructing contingency tables and performing chi-square analysis. Pooled data (meta-) analysis was performed with the Comprehensive Meta-Analysis v1.0.23 computer program (Biostat Inc.) using the Mantel-Haenszel method. Bonferroni corrections of statistical significance levels were performed using the Simple Interactive Statistical Analysis package.
Result Summary	In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

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

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs2306987	FAT1 CD36			Allelic P-value = 0.02, genotypic P-value = 0.005 in Aust case-control; Allelic P-value = 0.463, genotypic P-value = 0.439 in UK case-control; Allelic P-value = 0.084 in UK trios; Allelic P-value > 0.5 in Bulgarian trios for overall; Allelic P-value = 0.01, genotypic P-value = 0.004 in Aust case-control; Allelic P-value = 0.365, genotypic P-value = 0.592 in UK case-control; Allelic P-value = 0.06 in UK trios; Allelic P-value = 0.128 in Bulgarian trios with positive family history; Allelic P-value = 0.384, genotypic P-value = 0.228 in Aust case-control; Allelic P-value = 0.05, genotypic P-value = 0.022 in UK case-control with negative family history; Allelic P-value = 0.178, genotypic P-value = 0.261 in Aust case-control; Allelic P-value = 0.329, genotypic P-value = 0.484 in UK case-control; Allelic P-value = 0.003 in UK trios; Allelic P-value = 0.024 in Bulgarian trios with lifetime psychotic episode; Allelic P-value = 0.013, genotypic P-value = 0.005 in Aust case-control; Allelic P-value = 0.947, genotypic P-value = 0.298 in UK case-control; Allelic P-value > 0.5 in UK trios; Allelic P-value = 0.058 in Bulgarian trios with no psychotic episode; pooled P-value = 0.083, OR=1.19	The SNP provided statistically significant evidence for asso...... The SNP provided statistically significant evidence for association in the Australian case-control cohort. In the pooled data analysis, SNP rs2306987 showed weak evidence for association (P=0.06) with a summary OR of 1.27 (95% CI: 0.99-1.64).Statistically significant evidence for association was observed in the UK case-control cohort for those cases without a family history of mental illness. Neither the UK trios nor the Bulgarian trios showed evidence for association among family history or non-family history subsets. However, both trio cohorts did show statistically significant evidence for association among those bipolar cases who had exhibited psychosis More...	Positive
rs2304865	FAT1 CD36			Allelic P-value = 0.007, genotypic P-value = 0.009 in Aust case-control; Allelic P-value = 0.274, genotypic P-value = 0.542 in UK case-control for overall; Allelic P-value = 0.007, genotypic P-value = 0.006 in Aust case-control; Allelic P-value = 0.007, genotypic P-value = 0.025 in UK case-control with positive family history; Allelic P-value = 0.31, genotypic P-value = 0.528 in Aust case-control; Allelic P-value = 0.841, genotypic P-value = 0.975 in UK case-control with negative family history; Allelic P-value = 0.092, genotypic P-value = 0.176 in Aust case-control; Allelic P-value = 0.466, genotypic P-value = 0.487 in UK case-control with lifetime psychotic episode; Allelic P-value = 0.012, genotypic P-value = 0.011 in Aust case-control; Allelic P-value = 0.085, genotypic P-value = 0.079 in UK case-control with no psychotic episode; pooled P-value = 0.0002, OR=2.31	The SNP provided statistically significant evidence for asso...... The SNP provided statistically significant evidence for association in the Australian case-control cohort. In the pooled data analysis, SNP rs2304865 showed significant evidence for association (P=0.0002) with a summary odds ratio (OR) of 2.31 and remained significant after applying a Bonferroni correction for multiple testing. No case-control cohort showed evidence for association among psychosis or non-psychosis subsets. More...	Positive
rs1298865	FAT1 CD36			Allelic P-value = 0.072, genotypic P-value = 0.044 in Aust case-control; Allelic P-value = 0.838, genotypic P-value = 0.147 in UK case-control for overall; Allelic P-value = 0.01, genotypic P-value = 0.007 in Aust case-control; Allelic P-value = 0.038, genotypic P-value = 0.078 in UK case-control with positive family history; Allelic P-value = 0.98, genotypic P-value = 0.639 in Aust case-control; Allelic P-value = 0.082, genotypic P-value = 0.02 in UK case-control with negative family history; Allelic P-value = 0.197, genotypic P-value = 0.382 in Aust case-control; Allelic P-value = 0.512, genotypic P-value = 0.194 in UK case-control with lifetime psychotic episode; Allelic P-value = 0.029, genotypic P-value = 0.009 in Aust case-control; Allelic P-value = 0.729, genotypic P-value = 0.272 in UK case-control with no psychotic episode; pooled P-value = 0.003, OR=1.44	The SNP provided statistically significant evidence for asso...... The SNP provided statistically significant evidence for association in the Australian case-control cohort. In the pooled data analysis, SNP rs1298865 also showed significant evidence for association (P=0.003) with a summary OR of 1.44 (95% CI: 1.13-1.83)and remained significant after applying a Bonferroni correction for multiple testing. No case-control cohort showed evidence for association among psychosis or non-psychosis subsets. More...	Positive

Haplotypes reported by this study for BD (count: 2)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs2304865 - rs2637777 - rs2306990 - rs1298865 - rs2306987	G-T-G-T-A	CD36	P-value = 0.045	The GTGTA haplotype is over-represented among cases. The GTGTA haplotype is over-represented among cases.	Positive
rs2304865 - rs2637777 - rs2306990 - rs1298865 - rs2306987	C-G-A-C-T	CD36	P-value = 0.012	The CGACT haplotype is under-represented among cases. The CGACT haplotype is under-represented among cases.	Positive

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