Figure 1.
Organization of the extended clock network.
The core clock oscillator is a set of ∼18 genes that encode for transcriptional regulators (middle). These proteins are organized in complex feedback loops with positive (green) and negative (red) limbs that generate the ∼24 hr rhythms in gene expression responsible for maintaining circadian rhythms. Upstream clock modulators influence the period and/or amplitude of rhythms by altering protein stability, cellular distribution, or phosphorylation of proteins within the core clock (top). Core clock transcriptional regulators generate expression rhythms in numerous downstream clock controlled genes that are not the “gears of the clock” involved in generating rhythms, but may be important effectors or “hands of the clock” (bottom).
Figure 2.
The method for clock gene and random gene analysis is summarized for three test sets.
The rate of association in SLEP was determined for sets of randomly selected genes that contained gene numbers similar to A) core clock genes and B) clock modulator genes. C) Pervasively rhythmic (PRCCGs), weakly rhythmic (WRCCGs) and non-rhythmic genes were directly compared. Of 9950 clock controlled genes, 5187 were rhythmic in 2–5 tissues. Genes of intermediate rhythmicity were not examined.
Table 1.
Core clock genes.
Table 2.
SNPs with psychiatric illness associations and their location relative to the most proximal clock gene.
Table 3.
BD-spectrum associated clock modulator genes.
Table 4.
Pervasively rhythmic clock-controlled genes associated with BD-spectrum illnesses.
Figure 3.
Overlap among clock genes, genes associated with BD spectrum illnesses by GWAS, and lithium-responsive genes.
For each set of genes, the % associated with BD spectrum illnesses by GWAS (blue), the % found to be lithium-responsive (red), and the overlap between these (purple) is shown for 18 core clock genes (A), 342 clock modulator genes (C) and 136 pervasively rhythmic clock controlled genes (CCGs) (E) compared to their respective randomly selected controls (B and D), CCGs that are less pervasively rhythmic (F), and genes with no evidence for rhythmicity (G). Gray indicates % of genes with no relationship to either BD or lithium response.
Table 5.
Summary of the extended clock gene set included in the overlap between BD-spectrum and lithium induction after FDR correction.