Circadian patterns of gene expression in the human brain and disruption in major depressive disorder

Jun Z. Li, Blynn G. Bunney, Fan Meng, Megan H. Hagenauer, David M. Walsh, Marquis P. Vawter, Simon J. Evans, Prabhakara V Choudary, Preston Cartagena, Jack D. Barchas, Alan F. Schatzberg, Edward G. Jones, Richard M. Myers, Stanley J. Watson, Huda Akil, William E. Bunney

Research output: Contribution to journalArticle

252 Scopus citations

Abstract

A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ∼12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1 (REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.

Original languageEnglish (US)
Pages (from-to)9950-9955
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number24
DOIs
StatePublished - Jun 11 2013

Keywords

  • Circadian rhythms
  • Depression
  • Microarray

ASJC Scopus subject areas

  • General

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    Li, J. Z., Bunney, B. G., Meng, F., Hagenauer, M. H., Walsh, D. M., Vawter, M. P., Evans, S. J., Choudary, P. V., Cartagena, P., Barchas, J. D., Schatzberg, A. F., Jones, E. G., Myers, R. M., Watson, S. J., Akil, H., & Bunney, W. E. (2013). Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. Proceedings of the National Academy of Sciences of the United States of America, 110(24), 9950-9955. https://doi.org/10.1073/pnas.1305814110