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

作者：Jun Z. Li, Blynn G. Bunney, Fan Meng, Megan Hastings Hagenauer, David Walsh, Marquis P. Vawter, Simon J. Evans, Prabhakara V. Choudary, Preston Cartagena, Jack D. Barchas, Alan F. Schatzberg, Edward G. Jones, R Myers, Stanley J. Watson, Huda Akil, William E. Bunney · 发表于：Proceedings of the National Academy of Sciences · 年份：2013 · DOI：10.1073/pnas.1305814110 · 被引用次数：612 · 研究领域：Circadian rhythm and melatonin、Tryptophan and brain disorders、Health, Environment, Cognitive Aging

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 demonstrate...