Study Report

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Basic Info

Reference	Fullerton, J. M.,2010 PMID: 20712757
Citation	Fullerton, J. M., Y. Tiwari, et al. (2010). "Assessing oxidative pathway genes as risk factors for bipolar disorder." Bipolar Disord 12(5): 550-556.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	325 individuals diagnosed with bipolar spectrum disorder and 392 controls
SNP/Region/Marker Size	7 SNPs
Predominant Ethnicity
Population	Australian

Detail Info

Sample Diagnosis	DSM and RDC
Sample Status	The Australian bipolar disorder case-control cohort was recruited as part of an ongoing bipolar genetics study via the Black Dog Institute, Prince of Wales Hospital and School of Psychiatry, University of New South Wales, Sydney, Australia). Most of the cases were selected from extended families that had been previously recruited for linkage analyses (14- 18), whereby one affected individual was selected from each family for the case-control cohort, with the rest of the cases recruited from a specialized bipolar disorder clinic. The cohort comprised 325 individuals diagnosed with bipolar spectrum disorder, including 218 individuals affected with bipolar I disorder (BPI), 71 with bipolar II disorder (BPII), 10 with schizoaffective disorder, manic type (SZMA), and 10 with recurrent unipolar depression (UP). For controls, a spouse or a completely unrelated pedigree member of each case was selected from the family recruits (n = 166). An additional independently ascertained cohort (n = 226) of non-psychiatrically assessed healthy individuals (Australian volunteer blood donors) was provided by Dr. J. A. Cavanaugh to augment the psychiatrically assessed controls. Each had completed a self-report general health survey.
Technique	genotyping
Statistical Method	Association analysis was performed with the PLINK v1.02 software, using narrow and broad disease models, where individuals diagnosed with either BPI or SZMA were considered affected under the narrow model (n = 240); the broad model included individuals diagnosed with BPI,SZMA, BPII, or UP (n = 325).Haplotype analysis was performed with standard association testing using the - -hap-assoc and - -chap options. Interaction analysis was performed using the - -epistasis option in PLINK and the Genetic Association Interaction Analysis (GAIA) software.
Result Summary	With the case-control design the distribution of alleles between the two groups did not approach statistical significance. The extended transmission disequilibrium test (ETDT) performed in our families did not show evidence for linkage disequilibrium. Parametric and non-parametric linkage analysis also did not provide support for linkage between any of the four loci and BPAD. Our data do not support the hypothesis that variation at the polymorphic CAG/CTG repeat loci ERDA-1, SEF2-1b, MAB21L or KCNN3 influence susceptibility to BPAD in our sample.

SNPs reported by this study for BD (count: 6)

SNP	Related Gene(s)	Risk Allele	Statistical Values	Author Comments	Result Category
rs4880	SOD2	A	Allelic association: X²=2.207, P-value = 0.137, OR=0.844 for broad model; X²=1.649, P-value = 0.199, OR=0.851	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs3792797	GPX3	A	Allelic association: X²=1.932, P-value = 0.165, OR=1.216 for broad model; X²=1.048, P-value = 0.306, OR=1.172	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs3170633	GCLM	T	Allelic association: X²=1.465, P-value = 0.226, OR=0.871 for broad model; X²=1.704, P-value = 0.192, OR=0.848	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs2301022	GCLM	T	Allelic association: BD patients vs.166 controls: under both the narrow (allelic P-value = 0.0076, genotypic P-value = 0.032) and broad models (allelic P-value = 0.0308, genotypic P-value = 0.102); BD patients vs.392 controls: X²=1.33, P-value = 0.249, OR=1.142 for broad model; X²=2.727, P-value = 0.099, OR=1.23	This allele frequency difference revealed population stratif...... This allele frequency difference revealed population stratification. More...	Trend
rs5746136	SOD2	T	Allelic association: X²=0.083, P-value = 0.774, OR=1.034 for broad model; X²=0.118, P-value = 0.731, OR=1.045	No significant association was observed in BD. No significant association was observed in BD.	Negative
rs8177435	GPX3	G	Allelic association: X²=0.806, P-value = 0.369, OR=1.105 for broad model; X²=0.281, P-value = 0.596, OR=1.067	No significant association was observed in BD. No significant association was observed in BD.	Negative

Haplotypes reported by this study for BD (count: 4)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs5746136 - rs4880	T-G	SOD2	Haplotype analysis:X<sup>2</sup>= 8.94, global P-value = 0.03 ; X<sup>2</sup>= 9.91, individual P-value = 0.002, OR = 3.257 for broad model	Significant association was found in BD. Significant association was found in BD.	Positive
rs3792797 - rs4880		GPX3 SOD2	Interaction analysis:genotype, at narrow additive interaction model (P-value = 0.008), after Bonferroni correction for multiple testing(P-value = 0.055)	No significant association was found . No significant association was found .	Negative
rs3170633 - rs2301022	C-T	GCLM	Haplotype analysis:X<sup>2</sup>= 3.82, individual P-value = 0.050, OR = 1.293 for narrow model.	No significant association was found . No significant association was found .	Negative
rs3792797 - rs8177435 - rs5746136 - rs4880		GPX3 SOD2	Haplotype analysis:OR = 2.247, X<sup>2</sup> = 9.526, P-value = 0.002026, corrected P-value = 0.029	Significant association was found in BD. Significant association was found in BD.	Positive

Other variants reported by this study for BD (count: 1)

Variant Name	Related Gene	Type	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
GCLC 5'UTR repeat	GCLC	microsatellite	multi-allelic microsatellite		Allelic association:X²=1.013, P-value = 0.314, OR=0.859 for broad model;X²=1.454, P-value = 0.228, OR=0.815	No significant association was observed in BD. No significant association was observed in BD.	Negative

Genes reported by this study for BD (count: 4)

Gene	Statistical Values/Author Comments	Result Category
GPX3	We provide evidence that an interaction at both the genotype and haplotype level between SOD2 and GP...... We provide evidence that an interaction at both the genotype and haplotype level between SOD2 and GPX3 further increases disease risk. More...	Positive
GCLM	The allele frequency differences in the two control groups suggest that further analysis of this gen...... The allele frequency differences in the two control groups suggest that further analysis of this gene is required in psychiatrically assessed cohorts to determine the possible involvement of GCLM as a risk gene for bipolar disorder. More...	Trend
GCLC	No association was detected with the gene encoding GCLC. No association was detected with the gene encoding GCLC.	Negative
SOD2	We provide evidence that haplotypes within SOD2 are associated with increased risk for bipolar disor...... We provide evidence that haplotypes within SOD2 are associated with increased risk for bipolar disorder and that an interaction at both the genotype and haplotype level between SOD2 and GPX3 further increases disease risk. More...	Positive

Gene-gene interactions reported by this study for BD (count: 1)

Gene Group	Markers	Statistical Values	Author Comments	Result Category
GPX3 SOD2	rs3792797 - rs4880; rs3792797 - rs5746136	Interaction analysis: for makers "rs3792797 - rs4880", genotype, at narrow additive interaction model (P-value = 0.008), after Bonferroni correction for multiple testing (P-value = 0.055); for markers "(rs3792797-rs8177435) - (rs5746136-rs4880)", OR = 2.247, X² = 9.526, P-value = 0.002026, corrected P-value = 0.029.	Significant association was found in BD. Significant association was found in BD.	Positive