John R. Kelsoe is a founder and holds equity in Psynomics, Inc.
Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder
Article first published online: 9 MAR 2006
Copyright © 2006 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 141B, Issue 3, pages 234–241, 5 April 2006
How to Cite
Nievergelt, C. M., Kripke, D. F., Barrett, T. B., Burg, E., Remick, R. A., Sadovnick, A. D., McElroy, S. L., Keck, P. E., Schork, N. J. and Kelsoe, J. R. (2006), Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am. J. Med. Genet., 141B: 234–241. doi: 10.1002/ajmg.b.30252
- Issue published online: 27 MAR 2006
- Article first published online: 9 MAR 2006
- Manuscript Accepted: 25 AUG 2005
- Manuscript Received: 14 FEB 2005
- Swiss National Science Foundation (to C.M.N.). Grant Numbers: 823A-061200, HL071123
- NIH (to D.F.K.). Grant Numbers: HL071123, AG15763, AG12364, HL61280
- NIH (to N.J.S.). Grant Numbers: HL054998-09, HL064777-06, HL069758-03, HLMH065571-02, HL074730-02, MH059567-05A2, MH068503-01A1, HL070137-01A1, AG023122-01
- NIH (to T.B.B.). Grant Number: MH067959
- NIH (to J.R.K.). Grant Numbers: MH47612, MH59567, MH68503, DA13769
- Department of Veterans Affairs (to J.R.K.)
- UCSD General Clinical Research Center (to J.R.K.). Grant Number: M01 RR00827
- manic-depressive illness;
- genetic linkage;
- genetic association;
Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1ε, DBP, GSK3β, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1ε. 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. © 2006 Wiley-Liss, Inc.