The relationship between circadian gene single nucleotide polymorphisms and clinical and behavioral assessments of sleep and rhythms and course of illness characteristics in subjects with bipolar type I disorder

Rhythm disruptions are core clinical features of bipolar disorder and have been hypothesized as underlying pathophysiological mechanisms of the illness. The disorder is often times marked by chronobiological fluctuations and disturbances. Certain course of illness characteristics, such as rapid cycling and seasonality, also suggest rhythm disturbances to be a component of the disorder.

All organisms exhibit rhythmic oscillations in a variety of physiological processes. These rhythms are largely regulated by the biological timing system. While the master timekeeping mechanism is the suprachiasmatic nucleus (SCN) of the hypothalamus, at the core of the circadian timing system are endogenous molecular clocks comprised of “clock genes”. Endogenous molecular clocks function as interconnected transcriptional and translational feedback loops. It is the rhythmic expression of circadian genes that result in the rhythmic properties (i.e., phase, period, amplitude) of endogenous clocks. The core molecular clock is structured as follows: clock circadian regulator (CLOCK) and aryl hydrocarbon receptor nuclear translocator like (ARNTL) form a heterodimer that act as positive regulators activating the transcription of period circadian regulator (PER) and cryptochrome circadian regulator (CRY) genes. PER and CRY proteins form a heterodimer which, in turn, inhibit the transcriptional activity of the CLOCK:ARNTL heterodimer. The resulting decrease in PER and CRY concentrations resets the cycle. The pushes and pulls of these transcriptional/translational feedback loops sustain the period of the circadian oscillator at a near 24-h period. This process is modulated by several factors like kinases such as glycogen synthase kinase 3 beta (GSK3B) and casein kinase 1 epsilon (CSNK1E). In addition to their central role as timekeepers, endogenous molecular clocks regulate the expression of clock-controlled output genes whose products are responsible for the temporal organization of physiological processes many of which are implicated in mood regulation. It is now accepted that virtually every cell contains an autonomous circadian clock and that the circadian timing system is comprised not of one central loop but rather multiple interconnected loops.

In their preeminent textbook, Manic-Depressive Illness, Goodwin and Jamison postulated that “the genetic defect in manic depressive illness involves the circadian pacemaker or systems that modulate it” [10]. As a complex trait disorder [11], multiple genetic risk factors are likely associated with the development of bipolar disorder. Circadian genes are plausible candidate genes for bipolar disorder [10]. It has been proposed that the phenotypic expression of certain diseases may be related to the functioning of molecular clocks [12]. From a phenotypic standpoint, circadian gene variants may impact the expression of bipolar disorder. Circadian gene polymorphisms have been associated with recurrence rates and cycling patterns [13], [14], insomnia [13], [15], age at illness onset [16], diurnal patterns of mood expression [13], and response to treatments such as sleep deprivation [16] and lithium [17].

We, therefore, designed a proof-of-concept study to assess the relationship between circadian gene single nucleotide polymorphisms (SNPs) and clinical and behavioral assessments of sleep and rhythms and course of illness characteristics in subjects with bipolar type I disorder (BDI).