Is Bipolar Disorder a Circadian Rhythm Problem?

By Hannah Dunbar

(Brain Post Note: Hannah Dunbar is a Oral Roberts University undergraduate student who is doing a summer research elective with me. She will be providing some guest posts over the next two months related to her interest in sleep and bipolar disorder.)

Bipolar disorder is commonly characterized by sleep fluctations and distrubance of a regular circadian rhythm. It is logical to explore the role of circadian clock genes in bipolar disorder genetic studies. Pediatric bipolar disorder populations exhibit frequent mood cycling and sleep dysregulation making them an important subgroup to target for clock gene studies. Pediatric bipolar disorder is challenging to diagnose emphasizing the importance of more valid biomarkers or genetic risk markers.

McGrath and colleagues from the Center for Human Genetic research, Massachusetts General Hospital and collaborators from other institutions, recently published a study of several clock genes in a pediatric bipolar sample. Previous animal studies conducted by McGrath and colleagues, examined the role of the D-box binding protein (DBP), a stress-reactive gene associated with the expression of clock genes. A microarray study of the expression of two DBP-related clock genes (RAR-related orphan receptors alpha (RORA) and beta (RORB)), showed an alteration in the expression of these genes in a knockout mice experiment.

To extend these animal studies, this pediatric bipolar study used a family trio and case-control sampling design:

• One group included a family-based sample of 153 trios (each trio consisting of an affected BP proband and both parents)
• A second group included a sample of 152 pediatric bipolar cases (all independent from the trio samples)
• The second group was compared to 140 independent healthy controls (HC)
• BD subjects met DSM-IV criteria for bipolar disorder including (a) experiencing a distinct period of extreme and persistently elevated, expansive, or irritable mood lasting at least a week and (b) exhibiting 3 (4 if the mood is irritable only) out of 7 symptoms during the period of mood disturbance.

Results: Four intronic RORB SNPs were associated with the pediatric bipolar phenotype in the case-control sample but not the trio sample. The association persisted after Bonferroni correction for multiple statistical tests. An additional 11 SNPs were tied to bipolar phenotype using three RORB haplotype blocks. These associations were also not replicated in the trio sample. No association of RORA SNPs were found with bipolar phenotype.

Implications and Limitations: Isoforms of RORB, including RORB1 and RORB2 are thought to be produced via alternative forms of promoters during transcription. These isoforms are found exclusively in the retina and pineal gland, two essential regions in the light-stimulated production pathway of the sleep-wake hormone melatonin. Retinoid-related receptors (RORA and RORB) are involved in a number of synthetic pathways such as neurogenesis, stress response, and regulation of circadian rhythm. Alteration in the expression of these isoforms may influence some of the sleep dysregulation found in bipolar disorder. It is disappointing that SNP findings for the identified regions could not be confirmed in both bipolar samples. However, this study lends support for further research examining the role of biological clock mechanisms in bipolar disorder.

Photo of Mallard in Pool Courtesy of Yates Photography

McGrath, C., Glatt, S., Sklar, P., Le-Niculescu, H., Kuczenski, R., Doyle, A., Biederman, J., Mick, E., Faraone, S., Niculescu, A., & Tsuang, M. (2009). Evidence for genetic association of RORB with bipolar disorder BMC Psychiatry, 9 (1) DOI: 10.1186/1471-244X-9-70

Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB, Kuczenski R, & Niculescu AB (2004). Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Molecular psychiatry, 9 (11), 1007-29 PMID: 15314610