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	Shi, J., 2008 (d) PMID: 18228528
Citation	Shi, J., J. K. Wittke-Thompson, et al. (2008). "Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm." Am J Med Genet B Neuropsychiatr Genet 147B(7): 1047-1055.
Disease Type	Bipolar Disorder
Study Design	family-based
Study Type	Candidate-gene association study
Sample Size	A total of 416 samples were included in a modest-sized BPsample set (Sample I). Sample II consists of 1,158 individuals, including 70 trios and 237 quads, which includes the same 114 families but not necessarily the same individuals as Sample I.
SNP/Region/Marker Size	19 SNPs within five circadian genes in a modest-sizedBPsample set (Sample I); 62 SNPs within ten circadian genes in the extended BP family sample (Sample II).
Predominant Ethnicity	Caucasian
Population	CNG, NIMH and the CHIP collections
Gender	Of 194 offspring in sample I, 105 are females and 89 are males. Of 544 affected offspring in sample II, 326 are females and 218 are males.

Detail Info

Sample Diagnosis	Diagnostic Instrument for Genetic Studies (DIGS) and the Family Interview for Genetic Studies (FIGS); DSM-III-R or DSM-IV.
Sample Status	Of 194 offspring, 154 meet DSM-III-R criteria for BPI, 29 for BPII, and 11 for schizoaffective disorder bipolar type (SAB) in Sample I. Of 544 affected offspring from 70 trios and 237 quads, 481 had BPI, 37 had BPII, and 26 had SAB in Sample II.
Technique	genotyping
Statistical Method	Pairwise LD, using the standard LD coefficient D', was calculated between every pair of markers in each gene using Haploview (version 4.0). Haplotype blocks were identified using the solid spine of LD method in Haploview. Allelic association of individual SNPs was tested using the sib_tdt program in the program package ASPEX 2.5. Haplotypic association tests were carried out using PDTPHASE, in the program package UNPHASED. To evaluate interactions between genes without significant main effects, we used the ''focused interaction testing framework'' (FITF) method. We also tested, separately, gene-gene interaction among 10 genes in Sample II as this is a larger sample set. Multiple testing was corrected by the false discovery rate (FDR), which is designed to reduce the proportion of all positive results that are false and is less conservative (has a less negative effect on power) than the Bonferroni correction. Significant results were then tested using a betaversion of MDR-PDT.
Result Summary	In Sample II, the Sibling- Transmission Disequilibrium Test (sib-tdt) analysis showed nominally significant association of BP with three SNPs within or near the CLOCK gene (rs534654, P=0.0097; rs6850524, P=0.012; rs4340844, P=0.015). In addition, SNPs in the ARNTL2, CLOCK, DBP, and TIMELESS genes and haplotypes in the ARNTL, CLOCK, CSNK1E,and TIMELESS genes showed suggestive evidence of association with several circadian phenotypes identified in BP patients. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. A multi-locus interaction between rs6442925 in the 5' upstream of BHLHB2, rs1534891 inCSNK1E, and rs534654 near the 3' end of the CLOCK gene, however, is significantly associated with BP. It remains significant after correcting for multiple testing using the False Discovery Rate method. Our results indicate an interaction between three circadian genes in susceptibility to bipolar disorder.

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

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs7660668	CLOCK RN7SKP30	C/G		Allelic TDT P-value = 0.59 in bipolar disorder (Sample II)		Negative
rs6850524	CLOCK	C/G		Allelic TDT P-value = 0.012 in bipolar disorder (Sample II)	In Sample II, which is larger, three SNPs (rs534654, rs68505...... In Sample II, which is larger, three SNPs (rs534654, rs6850524, and rs4340844) at the CLOCK gene region showed suggestive evidence for transmission disequilibrium. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. More...	Positive
rs534654	CLOCK TMEM165	A/G		Allelic TDT P-value = 0.0097 in bipolar disorder (Sample II)	In Sample II, which is larger, three SNPs (rs534654, rs68505...... In Sample II, which is larger, three SNPs (rs534654, rs6850524, and rs4340844) at the CLOCK gene region showed suggestive evidence for transmission disequilibrium. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. More...	Positive
rs4340844	CLOCK	A/C		Allelic TDT P-value = 0.015 in bipolar disorder (Sample II)	In Sample II, which is larger, three SNPs (rs534654, rs68505...... In Sample II, which is larger, three SNPs (rs534654, rs6850524, and rs4340844) at the CLOCK gene region showed suggestive evidence for transmission disequilibrium. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. More...	Positive
rs2412648	CLOCK TMEM165	A/C		Allelic TDT P-value = 0.12 in bipolar disorder (Sample II)		Negative
rs11735267	CLOCK	A/G		Allelic TDT P-value = 0.059 in bipolar disorder (Sample II)		Negative

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

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
rs2137947 - rs6850524 - rs1534891		DEC1 CLOCK CSNK1E	FDR-cutoff P-value = 1.77E 06; FITF P-value = 7.59E 05		Negative
rs6442925 - rs714359 - rs16965644		DEC1 CRY1 NR1D1	FDR-cutoff P-value = 1.77E 06; FITF P-value = 8.88E 06		Negative
rs534654 - rs2412648 - rs4340844 - rs11735267 - rs6850524 - rs7660668	GACAGC	CLOCK	P-value = 0.028	Several haplotypes consisting of six SNPs at the CLOCK gene ...... Several haplotypes consisting of six SNPs at the CLOCK gene region also showed nominal association with disease. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. More...	Positive
rs534654 - rs2412648 - rs4340844 - rs11735267 - rs6850524 - rs7660668	AAAGCC	CLOCK	P-value = 0.034	Several haplotypes consisting of six SNPs at the CLOCK gene ...... Several haplotypes consisting of six SNPs at the CLOCK gene region also showed nominal association with disease. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. More...	Positive
rs6442925 - rs534654 - rs135757		DEC1 TMEM165 CSNK1E	FDR-cutoff P-value = 1.77E 06; FITF P-value = 2.62E 05		Negative
rs6442925 - rs534654 - rs1534891		DEC1 TMEM165 CSNK1E	FDR-cutoff P-value = 1.77E 06; FITF P-value = 1.72E 06	A significant multi-locus interaction between rs6442925 in B...... A significant multi-locus interaction between rs6442925 in BHLHB2, rs1534891 in CSNK1E, and rs534654 near 3' of CLOCK gene was identified in Sample II, which remained significant after correction for multiple testing using a false discovery rate method. More...	Positive
rs534654 - rs2412648 - rs4340844 - rs11735267 - rs6850524 - rs7660668	GAAACG	CLOCK	P-value = 0.025	Several haplotypes consisting of six SNPs at the CLOCK gene ...... Several haplotypes consisting of six SNPs at the CLOCK gene region also showed nominal association with disease. However, none of these associations reached gene-wide or experiment-wide significance after correction for multiple-testing. More...	Positive

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

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

Gene Group	Markers	Statistical Values	Author Comments	Result Category
DEC1 TMEM165 CSNK1E	rs6442925 - rs534654 - rs1534891; rs6442925 - rs534654 - rs135757	For markers "rs6442925 - rs534654 - rs1534891", FDR-cutoff P-value = 1.77E-06; FITF P-value = 1.72E-06. For markers "rs6442925 - rs534654 - rs135757", FDR-cutoff P-value = 1.77E-06; FITF P-value = 2.62E-05.	A significant multi-locus interaction between rs6442925 in B...... A significant multi-locus interaction between rs6442925 in BHLHB2, rs1534891 in CSNK1E, and rs534654 near 3' of CLOCK gene was identified in Sample II, which remained significant after correction for multiple testing using a false discovery rate method. More...	Positive
DEC1 CLOCK CSNK1E	rs2137947 - rs6850524 - rs1534891	FDR-cutoff P-value = 1.77E-06; FITF P-value = 7.59E-05		Negative
DEC1 CRY1 NR1D1	rs6442925 - rs714359 - rs16965644	FDR-cutoff P-value = 1.77E-06; FITF P-value = 8.88E-06		Negative