Study Report

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Basic Info

Reference	Byrne, E. M., 2014 PMID: 24687905
Citation	Byrne, E. M., et al. (2014). "Testing the role of circadian genes in conferring risk for psychiatric disorders." Am J Med Genet B Neuropsychiatr Genet.
Disease Type	Bipolar Disorder & Schizophrenia & MDD
Study Design
Study Type	Candidate-gene association study
Sample Size	Total sample sizes were 9,394 cases and 12,462 controls for SCZ, 7,481 cases and 9,250 controls for BD, and 9,240 cases and 9,519 controls for MDD.
SNP/Region/Marker Size	common variations for 21 circadian genes from PGC.
Predominant Ethnicity
Population	from PGC

Detail Info

Technique	If the reported SNPs were not in PGC data, we tried to identify a SNP in high linkage disequilibrium (LD) with the variant of interest. HapMap 2 for BPD and HapMap 3 for SCZ and MDD were used.
Statistical Method	SNP test is performed by a lookup of the single SNP test statistics in the PGC studies. A gene-based test of association was also carried out using the freely available software VEGAS.
Result Summary	After correcting formultiplecomparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of P<0.05, and none of the the variants identified in candidate studies of clock genes that were included in the PGC datasets were significant after correction for multiple testing. There was no evidence of an enrichment of associations in genes linked to control of circadian rhythms in human cells.

Genetic factors reported by this study for BD

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

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs4132063	CRY2			P-value=0.0006	The most significant single SNP association with BPD was wit...... The most significant single SNP association with BPD was with rs4132063(P=0.0006), a SNP located upstream of CRY2. More...	Negative
rs6746896	LMAN2L CNNM4			P-value=2.45E-09	The gene CNNM4 on chromosome 2 is located downstream of the ...... The gene CNNM4 on chromosome 2 is located downstream of the genome-wide significant SNP (rs6746896, BPD P=2.45*10-9) and ranks second among the extended circadian gene list for association with BPD. More...	Positive

Genes reported by this study for BD (count: 23)

Gene	Statistical Values/Author Comments	Result Category
CNNM4	The gene CNNM4 on chromosome 2 is located downstream of the genome-wide significant SNP (rs6746896, ...... The gene CNNM4 on chromosome 2 is located downstream of the genome-wide significant SNP (rs6746896, BPD P=2.45*10-9) and ranks second among the extended circadian gene list for association with BPD. More...	Positive
TUBA1B	P = 0.000002. The most significantly associated circadian gene with BPD is the TUBA1B gene on chromosome 12 (P=0.0...... The most significantly associated circadian gene with BPD is the TUBA1B gene on chromosome 12 (P=0.000002). More...	Positive
TIPIN	P-value=0.06. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
TIMELESS	P-value=0.27. It is notable that there are no SNPs in or near the TIMELESS gene that show evidence of association ...... It is notable that there are no SNPs in or near the TIMELESS gene that show evidence of association with risk to BPD, and similarly, the CLOCK gene harbors only one SNP that just reaches the nominal significance threshold (P=0.042), indicating that these genes are not strong candidates for influencing BPD risk in the population. More...	Negative
RORB	P-value=0.37. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
PER3	P-value=0.14. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
PER2	P-value=0.45. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
PER1	P-value=0.15. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
NR1D1	P-value=0.31. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
NPAS2	P-value=0.47. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
NFIL3	P-value=0.19. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
EGR3	P-value=0.10. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
DHX15	P-value=0.04. The evidence for a role for common risk variants in circadian genes is slightly stronger for BPD, wi...... The evidence for a role for common risk variants in circadian genes is slightly stronger for BPD, with two genesâ€”BHLHB3 and DBP1â€”showing nominal significance for the gene-based test and nine genes harboring a SNP with a P-value <0.01 More...	Positive
CSNK1E	P-value=0.83. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
CSNK2A1	P-value=0.20. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
CRY2	P-value=0.07. The most significant single SNP association with BPD was with rs4132063(P=0.0006), a SNP located ups...... The most significant single SNP association with BPD was with rs4132063(P=0.0006), a SNP located upstream of CRY2. More...	Negative
CSNK1D	P-value=0.60. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
CLOCK	P-value=0.29. It is notable that there are no SNPs in or near the TIMELESS gene that show evidence of association ...... It is notable that there are no SNPs in or near the TIMELESS gene that show evidence of association with risk to BPD, and similarly, the CLOCK gene harbors only one SNP that just reaches the nominal significance threshold (P=0.042), indicating that these genes are not strong candidates for influencing BPD risk in the population. More...	Negative
CNR1	P-value=0.11. When ranking genes based on the most significant SNP, the strongest signal was rs9353523 in the CNR1...... When ranking genes based on the most significant SNP, the strongest signal was rs9353523 in the CNR1 gene (P=0.001). More...	Negative
ARNTL2	P-value=0.36. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
BHLHE41	P-value=0.03. The evidence for a role for common risk variants in circadian genes is slightly stronger for BPD, wi...... The evidence for a role for common risk variants in circadian genes is slightly stronger for BPD, with two genesâ€”BHLHB3 and DBP1â€”showing nominal significance for the gene-based test and nine genes harboring a SNP with a P-value <0.01. More...	Positive
AANAT	P-value=0.71. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative
ARNTL	P-value=0.26. Gene-based tests show no significant association between this gene and BD. Gene-based tests show no significant association between this gene and BD.	Negative

Genetic factors reported by this study for SZ and/or MDD

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	CSNK2A1	P-value=0.67. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	ARNTL	P-value=0.53. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	PER3	P-value=0.24. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	DHX15	P-value=0.13. The results from the gene-based test indicate that DBP1 is the best candidates among the circadian genes to influence SCZ risk.	Negative
SZ	CSNK1D	P-value=0.38. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	TIPIN	P-value=0.88. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	PER1	P-value=0.40. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	NR1D1	P-value=0.64. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	BHLHE41	P-value=0.60. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	AANAT	P-value=0.17. The results from the gene-based test indicate that AANAT is the best candidates among the circadian genes to influence SCZ risk.	Negative
SZ	TIMELESS	P-value=0.33. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	CNR1	P-value=0.76. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	ARNTL2	P-value=0.42. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	RORB	P-value=0.21. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	CRY2	P-value=0.21. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	NFIL3	P-value=0.41. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	EGR3	P-value=0.77. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	NPAS2	P-value=0.87. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	CLOCK	P-value=0.98. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	PER2	P-value=0.52. Gene-based tests show no significant association between this gene and SZ.	Negative
SZ	CSNK1E	P-value=0.20. The results from the gene-based test indicate that CSNK1E is the best candidates among the circadian genes to influence SCZ risk.	Negative
MDD	CSNK2A1	P-value=0.80. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	ARNTL2	P-value=0.95. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	RORB	P-value=0.66. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	CRY2	P-value=0.68. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	ARNTL	P-value=0.51. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	PER3	P-value=0.64. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	DHX15	P-value=0.58. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	CSNK1D	P-value=0.58. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	NFIL3	P-value=0.16. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	EGR3	P-value=0.63. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	TIPIN	P-value=0.36. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	PER1	P-value=0.61. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	NR1D1	P-value=0.03. The NR1D1 gene was the only circadian gene to show nominal significancewith major depression(P=0.03).	Negative
MDD	BHLHE41	P-value=0.74. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	AANAT	P-value=0.24. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	NPAS2	P-value=0.39. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	CLOCK	P-value=0.54. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	TIMELESS	P-value=0.70. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	CNR1	P-value=0.12. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	PER2	P-value=0.67. Gene-based tests show no significant association between this gene and MDD.	Negative
MDD	CSNK1E	P-value=0.80. Gene-based tests show no significant association between this gene and MDD.	Negative