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Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Medical Genetics part B Wiley

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder

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References (54)

Publisher
Wiley
Copyright
Copyright © 2006 Wiley‐Liss, Inc., A Wiley Company
ISSN
1552-4841
eISSN
1552-485X
DOI
10.1002/ajmg.b.30252
pmid
16528748
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

American Journal of Medical Genetics part B – Wiley

Published: Apr 5, 2006

Keywords: manic‐depressive illness; genetic linkage; genetic association; PER3 ; BMAL1

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