Abstract
Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian “clock genes” associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential “core” clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.
Highlights
Bipolar disorder (BD) is a serious and life-threatening mental illness that affects 1–2% of the population
Strongly implicated by genome-wide association studies (GWAS), collectively they are associated with BD spectrum illnesses at a rate higher than would be expected by chance, i.e. there are more illness-associated genes among the 18 core clock genes than among sized control sets of randomly selected genes
This enrichment is limited to the core clock genes and their most pervasively rhythmic biological outputs, the PRCCGs, and does not extend to either the modulator genes that have been shown to alter clock period and amplitude [29], or to less pervasively rhythmic genes (WRCCGs)
Summary
Bipolar disorder (BD) is a serious and life-threatening mental illness that affects 1–2% of the population. Based upon clinical observations that patients with BD often exhibit evening chronotype, disturbances in periodic daily activities (e.g. decreased need for sleep, insomnia or hypersomnia, disturbed appetite, and disrupted daily activity patterns), and that mood episodes are affected by light and follow seasonal patterns, a circadian rhythm hypothesis of BD and depression has been developed [2]. This hypothesis has been supported by the development of a mouse model of BD in which a mutation in Clock, a core component of the cellular circadian clock, causes lithium-sensitive, mania-like behavioral abnormalities [3,4]. Glycogen synthase kinase 3b (GSK3b) is inhibited by lithium [10], and has been implicated in both lithium’s effect on circadian rhythms [11,12], and its therapeutic action in BD [13]
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