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

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, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. 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.

Circadian genes, rhythms and the biology of mood disorders

“…Haplotypes in BMAL1 and Per3 were found to significantly associate with BPD in one study (Nievergelt et al, 2006). Furthermore, a SNP in BMAL1 and a SNP in the Timeless gene have also been identified that associate with BPD (Mansour et al, 2006).…”

“…It should be noted that additional studies have found associations between members of the molecular clock and other psychiatric disorders such as schizophrenia and alcoholism, suggesting that these genes are important in a range of psychiatric conditions (Spanagel et al, 2005;Mansour et al, 2006). However, in general, most of these studies only find modest associations, and other studies that have examined SNPs throughout the sequence of some of the central members of the circadian clock have found no associations with these genes and any psychiatric disorders (Shiino et al, 2003;Nievergelt et al, 2005;Mansour et al, 2006;Nievergelt et al, 2006). Therefore the functional importance of these variations is still uncertain, and only certain members of the circadian clock may be involved.…”

Assessment of circadian function in fibroblasts of patients with bipolar disorder

“…Furthermore, suggestive evidence has recently been reported for the association of circadian gene variants including CLOCK, BMAL1, PER3 and TIMELESS with bipolar disorder. [31][32][33] Moreover, studies using pharmacogenomic animal models for bipolar disorder have revealed circadian genes as the candidate genes for mania and psychosis, which include BMAL1, GSK3b, CKId, CRY2 34 and DBP. 35 Despite the above-mentioned evidence implicating the circadian system in the pathophysiology of bipolar disorder, the functional and molecular basis of circadian anomalies in bipolar disorder has not been elucidated.…”

Novel functions for Period 3 and Exo-rhodopsin in rhythmic transcription and melatonin biosynthesis within the zebrafish pineal organ

“…In contrast, per3 knock out mice have only a slight decrease in the period of their circadian clock [51]. In humans, certain polymorphisms in the per3 gene and misregulation of per3 expression have been associated with breast cancer, chronic myeloid leukemia, bipolar disorder, and the structure of the sleep/wake cycle [15,41,58,61,62].…”