Mood and Psychosis Risk-Associated Genes Regulate Neuronal Circadian Rhythms Across the Transcriptome

Mood and psychotic disorders are associated with disrupted circadian rhythms in sleep and activity. While mood and psychosis risk-associated genes (MPRGs) have been linked with sleep and circadian phenotypes, their contributions to molecular clock pathways and cellular circadian rhythms remain unknown.

To understand how MPRGs affect temporal dynamics and contribute to circadian rhythms in transcription across the genome, we knocked down expression of ARNTL, ANK3, CACNA1C, or TCF4 in human iPSC-derived neuronal precursor cells (NPCs) from healthy donors. Gene expression was examined serially over 24 h using whole-transcriptome RNA sequencing. Rhythm and pathway analyses were performed to identify rhythmic genes, and gene sets impacted by MPRG knockdown using small interfering RNA (siRNA).

Each siRNA distinctly altered phase and/or amplitude of rhythmic genes. Knockdown of ARNTL resulted in widespread loss of rhythms in core clock and other genes but also caused unexpected gains in rhythm. CACNA1C knockdown increased the number of rhythmic genes. ANK3 and TCF4 knockdown had modest effects on gain/loss of rhythm, but caused significant phase shifts. Functional analyses revealed widespread changes in rhythmic genes previously implicated in mood and psychotic disorders, including synaptic transmission, cellular stress response, and gated ion channels.

Our findings are the first to indicate MPRGs contribute widely to neuronal circadian rhythms across the transcriptome. Altered rhythms may disrupt biological pathways implicated across a range of psychiatric disorders.