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	Nievergelt, C. M., 2006 PMID: 16528748
Citation	Nievergelt, C. M., D. F. Kripke, et al. (2006). "Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder." Am J Med Genet B Neuropsychiatr Genet 141B(3): 234-241.
Disease Type	Bipolar Disorder
Study Design	pedigree and family-based
Study Type	Candidate-region linkage study and candidate-gene association study
Sample Size	52 pedigrees from Set 1, consisting of 356 subjects in the linkage study, and a sample of 159 families (564 individuals) in the association study
SNP/Region/Marker Size	68 loci
Predominant Ethnicity
Population	UCSD/UBC/UC collection, NIMH collection

Detail Info

Sample Diagnosis	DSM-III-R
Sample Status	The UCSD/UBC/UC family set (Set 1) was collected at UCSD, the University of British Columbia, and the University of Cincinnati. Briefly, all families were collected through a bipolar I or II proband, and selected for the presence of at least two other mood disordered family members. The Structured Clinical Interview for DSM-III-R was used to directly interview subjects. Information from the interview, other family informants, and medical records were then reviewed by a panel of clinicians in order to make a best estimate diagnosis. In addition, 106 families from the NIMH Genetics Initiative for Bipolar Disorder first-wave pedigree collection were used (Set 2). All families were ascertained through a bipolar I proband, and the Diagnostic Interview for Genetic Studies was employed.
Technique	genotyping
Statistical Method	For the linkage study, we used CRI-MAP 2.4 to detect microsatellite genotyping errors (option 'chrompic'). Parametric two-point linkage analyses were performed using LINKAGE. Associations between the 52 markers and BPAD were evaluated with a transmission disequilibrium test (TDT). TDTPHASE analyzes single SNPs as well as haplotypes from unphased genotype data, and it performs permutation tests to assess significance by reassigning the transmitted and untransmitted labels.
Result Summary	Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1 epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

Haplotypes reported by this study for BD (count: 9)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs3789327 - rs2278749	A-T	ARNTL	phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.0005464, nominal P-value for the setting based on Chi-square test=0.00457, global permutated P-value = 0.02597, Bonferroni corrected P-value = 0.234; estimation of missing parental genotypes in addition to uncertain haplotypes: P-value associated with the haplotype=0.001395, nominal P-value for the setting based on Chi-square test=0.00379, global permutated P-value = 0.02498, Bonferroni corrected P-value = 0.225	Suggestive evidence for association was found in the gene AR...... Suggestive evidence for association was found in the gene ARNTL for an under-transmitted single haplotype comprised of the intronic markers 4 (rs3789327) and 5 (rs2278749) as part of the two-marker window analysis with settings 2 (PG=0.02597) and 3 (PG=0.02498), respectively. More...	Positive
rs228642 - rs228666 - rs228696 - rs2859388 - rs11576985	T-C-C-A-4	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.003858, nominal P-value for the setting based on Chi-square test=0.0144, global permutated P-value = 0.04895, Bonferroni corrected P-value = 0.441; phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.01645, nominal P-value for the setting based on Chi-square test=0.00958, global permutated P-value = 0.03097, Bonferroni corrected P-value = 0.279	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive
rs228642 - rs228666 - rs228696 - rs2859388 - rs11576985	C-C-C-G-4	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.008638; phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.01037	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive
rs228642 - rs228666 - rs228696 - rs2859388 - rs11576985	C-T-C-A-5	PER3	phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.01517	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive
rs228666 - rs228696 - rs2859388 - rs11576985	C-C-A-4	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.002118, nominal P-value for the setting based on Chi-square test=0.00759, global permutated P-value = 0.03197, Bonferroni corrected P-value = 0.288	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive
rs228666 - rs228696 - rs2859388 - rs11576985	C-C-G-4	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.031	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive
rs228729 - rs228642 - rs228666 - rs228696 - rs2859388 - rs11576985	C-T-C-C-A-4	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.00385, nominal P-value for the setting based on Chi-square test=0.00965, global permutated P-value = 0.01898, Bonferroni corrected P-value = 0.171; phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.01241, nominal P-value for the setting based on Chi-square test=0.00804, global permutated P-value = 0.00799, Bonferroni corrected P-value = 0.072; estimation of missing parental genotypes in addition to uncertain haplotypes: P-value associated with the haplotype=0.0148, nominal P-value for the setting based on Chi-square test=0.02103, global permutated P-value = 0.03596, Bonferroni corrected P-value = 0.324	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. The strongest evidence was found on haplotypes including all six markers (PG=0.00799) and was almost reaching Bonferroni-corrected significance (PGC=0.072). More...	Positive
rs228729 - rs228642 - rs228666 - rs228696 - rs2859388 - rs11576985	C-C-C-C-G-4	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.008638; phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.01036; estimation of missing parental genotypes in addition to uncertain haplotypes: P-value associated with the haplotype=0.03067	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive
rs228729 - rs228642 - rs228666 - rs228696 - rs2859388 - rs11576985	T-C-T-C-A-5	PER3	phase-certain haplotypes: P-value associated with the haplotype=0.1755; phase-certain and uncertain haplotypes: P-value associated with the haplotype=0.01516; estimation of missing parental genotypes in addition to uncertain haplotypes: P-value associated with the haplotype=0.0293	Suggestive evidence for association was found in the four, f...... Suggestive evidence for association was found in the four, five, and six marker window analyses in all three analysis settings, with one under-transmitted haplotype and one to two overtransmitted haplotypes. More...	Positive

Genes reported by this study for BD (count: 10)

Gene	Statistical Values/Author Comments	Result Category
GSK3B	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative
PER1	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative
NPAS2	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative
ARNTL	Single SNP TDT analyses showed no evidence for association to BPAD. Haplotypes in ARNTL and PER3 wer...... Single SNP TDT analyses showed no evidence for association to BPAD. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests. More...	Positive
PER3	Single SNP TDT analyses showed no evidence for association to BPAD. Haplotypes in ARNTL and PER3 wer...... Single SNP TDT analyses showed no evidence for association to BPAD. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests. More...	Positive
PER2	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative
DBP	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative
CRY2	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative
CSNK1E	Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. Thi...... Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. More...	Trend
CLOCK	Single SNP TDT analyses showed no evidence for association to BPAD. Single SNP TDT analyses showed no evidence for association to BPAD.	Negative

Regions reported by this study for BD (count: 8)

Region	Statistical Values	Author Comments	Result Category
11p15	LOD = -6.63 for marker D11S4116 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -3.49 at Theta = 0.05 for the narrow diagnostic and AR50 genetic model, LOD = -1.93 at Theta = 0.1 for the narrow diagnostic and AR50 genetic model; LOD = -5.64 for marker D11S4170 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -2.09 at Theta = 0.05 for the narrow diagnostic and AD50 genetic model, LOD = -0.69 at Theta = 0.1 for the narrow diagnostic and AD50 genetic model		Negative
17p13.1-17p12	LOD = -11.69 for marker D17S1828 at Theta = 0 for the broad diagnostic and AR50 genetic model, LOD = -7.55 at Theta = 0.05 for the broad diagnostic and AR50 genetic model, LOD = -4.97 at Theta = 0.1 for the broad diagnostic and AR50 genetic model; LOD = -4.24 for marker D17S1353 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -0.68 at Theta = 0.05 for the narrow diagnostic and AD50 genetic model, LOD = 0.13 at Theta = 0.1 for the narrow diagnostic and AD50 genetic model		Negative
19q13.3	LOD = -3.48 for marker D19S606 at Theta = 0 for the broad diagnostic and AR50 genetic model, LOD = -1.26 at Theta = 0.05 for the broad diagnostic and AR50 genetic model, LOD = -0.18 at Theta = 0.1 for the broad diagnostic and AR50 genetic model; LOD = -6.67 for marker D19S867 at Theta = 0 for the broad diagnostic and AR50 genetic model, LOD = -3.8 at Theta = 0.05 for the broad diagnostic and AR50 genetic model, LOD = -2.14 at Theta = 0.1 for the narrow diagnostic and AR50 genetic model		Negative
1p36.23	LOD = -8.54 for marker D1S2663 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -4.43 at Theta = 0.05 for the narrow diagnostic and AR50 genetic model, LOD = -2.27 at Theta = 0.1 for the narrow diagnostic and AD50 genetic model; LOD = -7.34 for marker D1S1612 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -3.84 at Theta = 0.05 for the narrow diagnostic and AR50 genetic model, LOD = -2.05 at Theta = 0.1 for the narrow diagnostic and AR50 genetic model		Negative
22q13.1	LOD = 0.07 for marker D22S283 at Theta = 0 for the narrow diagnostic and AD50 genetic model; LOD = 1.92 at Theta = 0.05 for the narrow diagnostic and AD50 genetic model; LOD = 2.22 at Theta = 0.1 for the narrow diagnostic and AD50 genetic model; LOD = -8.16 for marker D22S423 at Theta = 0 for the broad diagnostic and AR50 genetic model; LOD = -3.28 at Theta = 0.05 for the broad diagnostic and AD50 genetic model; LOD = -1.62 at Theta = 0.1 for the broad diagnostic and AD50 genetic model	With the exception of D22S283, no positive LOD scores were o...... With the exception of D22S283, no positive LOD scores were obtained under any of the six models for the overall marker versus disease analysis. A maximum LOD of 2.22, which is suggestive for linkage, was obtained for D22S283 at Theta=0.1 for the narrow diagnostic and AD50 genetic model. More...	Trend
2q37.3	LOD = -3.81 for marker D2S345 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -1.98 at Theta = 0.05 for the narrow diagnostic and AR50 genetic model, LOD = -0.97 at Theta = 0.1 for the narrow diagnostic and AR50 genetic model; LOD = -10.16 for marker D2S2338 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -6.19 at Theta = 0.05 for the narrow diagnostic and AR50 genetic model, LOD = -3.91 at Theta = 0.1 for the narrow diagnostic and AR50 genetic model		Negative
4q12	LOD = -4.56 for marker D4S3000 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -1.7 at Theta = 0.05 for the narrow diagnostic and AD50 genetic model, LOD = -0.63 at Theta = 0.1 for the narrow diagnostic and AD50 genetic model; LOD = -9.32 for marker D4S1569 at Theta = 0 for the narrow diagnostic and AD50 genetic model, LOD = -4.37 at Theta = 0.05 for the narrow diagnostic and AD50 genetic model, LOD = -2.43 at Theta = 0.1 for the narrow diagnostic and AD50 genetic model		Negative
11p11.2	LOD = -6.46 for marker D11S1785 at Theta = 0 for the broad diagnostic and AR50 genetic model, LOD = -3.8 at Theta = 0.05 for the broad diagnostic and AR50 genetic model, LOD = -2.26 at Theta = 0.1 for the broad diagnostic and AR50 genetic model; LOD = -6.54 for D11S4109 at Theta = 0 for the narrow diagnostic and AR50 genetic model, LOD = -3.24 at Theta = 0.05 for the narrow diagnostic and AR50 genetic model, LOD = -1.63 at Theta = 0.1 for the narrow diagnostic and AR50 genetic model		Negative