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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Basic Info

Reference	Jan, W. C., 2014 PMID: 24581832
Citation	Jan, W. C., et al. (2014). "Exploring the associations between genetic variants in genes encoding for subunits of calcium channel and subtypes of bipolar disorder." J Affect Disord 157: 80-86.
Disease Type	Bipolar Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	200 BP-I and 80 BP-II patients, and 200 healthy controls
SNP/Region/Marker Size	16 SNPs
Predominant Ethnicity	Mongloid
Population	Taiwanese
Gender	43.5% (200) male in BP-I and 61.3% (80) male in BP-II patients, and 31.0% (200) male in healthy controls
Age Group	adults : mean age=36.27, SD=11.9 years of BP-I patients and mean age= 31.47, SD=11.0 years of of BP-II patients; mean age=47.37, SD=8.7 years of controls.

Detail Info

Sample Diagnosis	DSM-IV
Sample Status	Clinical patients who met the diagnostic criteria of major depression disorder (MDD), bipolar I disorder (BP-I), or bipolar II disorder (BP-II) according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) were consecutively referred by psychiatrists. Index probands whose age is between 18 and 70 years and their biological parents were Han Chinese were recruited. We excluded patients with diagnosis of schizophrenia, schizoaffective or substance-induced mood disorders.
Replication Size	495 BP-I patients and 1341 controls in the replication samples
Technique	Use customized Illumina GoldenGates Genotyping Assay with VeraCodeTM Technology to design selected sixteen SNPs. We then adopted TaqMans SNP genotyping assay (Applied Biosystems) for these three SNPs. Remaining thirteen SNPs were genotyped using the Illumina GoldenGates array at the National Taiwan University Center for Biotechnology.
Statistical Method	The associations between two subtypes of the BP and genetic variants were analyzed using a maximum test with logistic regression models, which includes the additive, recessive and dominant modes of inheritance. We calculated empirical P-values for each marker using permutation procedure in PLINK v1.07. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in regression models. Structures of linkage disequilibrium (LD) blocks and haplotypic associations were analyzed using Haploview version 4.2 software. Interaction tests among SNPs in the discovery samples were performed by method of multifactor dimensionality reduction, MDR. We used MACH1.0 to impute a few missing genotypes before running MDR. For replication, the same single marker analysis was performed for markers rs11013860 and rs10848635 in the replication samples, and a combined P-value was calculated using Fisher's method for the four independent samples.
Result Summary	Weak associations for CACNA1C (rs10848635), CACNA1E (rs10848635), CACNB2 (rs11013860), and CACNG2 (rs2284018) genes were observed. Joint analysis of four markers revealed higher accumulative risk with increasing numbers of risk genotypes an individual endorsed for BP-I (Ptrend=0.006) and BP-II (Ptrend=0.017) disorders. Combined analysis with independent replication samples further supported the association of rs11013860 in CACNB2 with BP subtype I (P=1*10-6). Suggestive interactions were found between genes encoded for different subunits of calcium channel (_1, _, and _).

SNPs reported by this study for BD (count: 13)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs1006737	CACNA1C	G/A		HWE; OR=0.5, 95%CI=0.05-5.59, P-value=0.58 for BD-I; OR=1.79, 95%CI=0.7-4.17, P-value=0.18 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs704326	CACNA1E	G/A		OR=1.8, 95%CI=1.00-3.26, P-value=0.049 for BD-I; OR=0.83, 95%CI=0.42-1.64, P-value=0.6 for BD-II.	The missense SNP, rs704326 in CACNA1E demonstrated a weak as...... The missense SNP, rs704326 in CACNA1E demonstrated a weak association with BP-I (OR=1.80, P=0.049, empirical P=0.053). More...	Positive
rs10848635	CACNA1C	T/A		OR=1.85, 95%CI=0.96-3.57, P-value=0.06 for BD-I; OR=2.69, 95%CI=1.26-5.76, P-value=0.01 for BD-II. P-value = 0.170 for combined analysis.	Homozygous of minor allele of rs10848635 in CACNA1C had an i...... Homozygous of minor allele of rs10848635 in CACNA1C had an increased risk for BP-I and BP-II, though only BP-II showed a nominal P-value less than 0.05 (OR=2.69, empirical P=0.069). More...	Positive
rs4915476	CACNA1S	G/A		OR=1.35, 95%CI=0.76-2.39, P-value=0.3 for BD-I; OR=0.74, 95%CI=0.31-1.81, P-value=0.51 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs16847674	CACNA1S	G/A		OR=0.58, 95%CI=0.17-2.02, P-value=0.39 for BD-I; OR=1.14, 95%CI=0.29-4.51, P-value=0.86 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs3850625	CACNA1S	G/A		OR=1.24, 95%CI=0.51-3.03, P-value=0.63 for BD-I; OR=1.43, 95%CI=0.46-4.4, P-value=0.54 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs12139527	CACNA1S	A/G		OR=1.14, 95%CI=0.73-1.77, P-value=0.57 for BD-I; OR=1.57, 95%CI=0.17-14.25, P-value=0.69 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs11013860	CACNB2	C/A		OR=1.36, 95%CI=1.02-1.81, P-value=0.04 for BD-I; OR=1.3, 95%CI=0.75-2.25, P-value=0.36 for BD-II. P-value = 1.04E-06 for the combined analysis.	For the Î² subunit, marker rs11013860 in CACNB2 genewas asso...... For the Î² subunit, marker rs11013860 in CACNB2 genewas associated with BP-I (OR=1.36, P=0.04, empirical P=0.038). More...	Positive
rs1799938	CACNG1	G/A		OR=2, 95%CI=0.18-22.24, P-value=0.57 for BD-I; OR=1.2, 95%CI=0.61-1.68, P-value=0.59 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs2284017	CACNG2	G/A		OR=1.1, 95%CI=0.82-1.49, P-value=0.53 for BD-I; OR=0.79, 95%CI=0.38-1.66, P-value=0.54 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs2284018	CACNG2	G/A		OR=1.14, 95%CI=0.76-1.71, P-value=0.53 for BD-I; OR=1.82, 95%CI=2.87-1.15, P-value=0.01 for BD-II.	For the Î³ subunit, marker rs2284018 in CACNG2 gene showed s...... For the Î³ subunit, marker rs2284018 in CACNG2 gene showed significant association with BP-II only (OR=1.82, P=0.01, empirical P=0.009). More...	Positive
rs5750285	CACNG2	C/G		OR=1.2, 95%CI=0.72-2.01, P-value=0.48 for BD-I; OR=0.79, 95%CI=0.38-1.65, P-value=0.53 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative
rs2286677	CACNG5	G/A		OR=0.73, 95%CI=0.16-3.29, P-value=0.68 for BD-I; OR=1.59, 95%CI=0.82-3.08, P-value=0.17 for BD-II.	Results of single marker association tests. Results of single marker association tests.	Negative

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

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs2284017 - rs2284018 - rs5750285	A-G-G	CACNG2	12.5% in BP-I cases vs.10.4% in controls, 19.2% in BP-II cases vs.10.5% in controls. The haplotype had grequency greater than 0.01.	Only one LD block in CACNG2 were found (formed by rs2284017-...... Only one LD block in CACNG2 were found (formed by rs2284017-rs2284018- rs5750285) in which three haplotypes had frequency greater than 0.01. Consistent with single marker analysis, haplotype AGG showed similar association with BP-I (12.5% in cases vs. 10.4% in controls), and BP-II (19.2% in cases vs. 10.5% in controls). More...	Positive

Genes reported by this study for BD (count: 7)

Gene	Statistical Values/Author Comments	Result Category
CACNG5	No marker in this gene was found to the significant. No marker in this gene was found to the significant.	Negative
CACNG2	Weak associations for CACNG2 (rs2284018) genes were observed. Weak associations for CACNG2 (rs2284018) genes were observed.	Positive
CACNG1	No marker in this gene was found to the significant. No marker in this gene was found to the significant.	Negative
CACNB2	Weak associations for CACNB2 (rs11013860) genes were observed. Weak associations for CACNB2 (rs11013860) genes were observed.	Positive
CACNA1S	No marker in this gene was found to the significant. No marker in this gene was found to the significant.	Negative
CACNA1E	Weak associations for CACNA1E (rs10848635) genes were observed. Weak associations for CACNA1E (rs10848635) genes were observed.	Positive
CACNA1C	Weak associations for CACNA1C (rs10848635) genes were observed. Weak associations for CACNA1C (rs10848635) genes were observed.	Positive

Gene-gene interactions reported by this study for BD (count: 3)

Gene Group	Markers	Statistical Values	Author Comments	Result Category
CACNA1E CACNB2	rs704326 - rs11013860	Training Bal. Acc. (%) = 0.5781, Testing Bal. Acc. (%)= 0.5225	The 2-locus model was considered the best model as it had th...... The 2-locus model was considered the best model as it had the highest cross-validation consistency and acceptable testing-balanced accuracy, involving rs704326 in CACNA1E and rs11013860 in CACNB2. Both of the two markers showed weak associations with BP-I in previous single locus association analysis. More...	Trend
CACNA1E CACNB2 CACNG2	rs704326 - rs11013860 - rs5750285	Training Bal. Acc. (%) = 0.6125, Testing Bal. Acc. (%)= 0.4425		Trend
CACNA1E CACNB2 CACNG2 CACNA1C	rs704326 - rs11013860 - rs5750285 - rs10848635	Training Bal. Acc. (%) = 0.6681, Testing Bal. Acc. (%)= 0.4525	The 4-loci interaction model showed high training accuracy b...... The 4-loci interaction model showed high training accuracy but moderate cross validation consistency of 6 out of 10 tests. The four loci were rs704326, rs11013860, rs10848635, and rs5750285; three of them were reported to be associated with BP at single marker level. More...	Trend