title: Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.
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.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. junzli@med.umich.edu
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.forename: Blynn G
authors.initials: BG
authors.lastname: Bunney
authors.forename: Fan
authors.initials: F
authors.lastname: Meng
authors.forename: Megan H
authors.initials: MH
authors.lastname: Hagenauer
authors.forename: David M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Evans
authors.forename: Prabhakara V
authors.initials: PV
authors.lastname: Choudary
authors.forename: Preston
authors.initials: P
authors.lastname: Cartagena
authors.forename: Jack D
authors.initials: JD
authors.lastname: Barchas
authors.forename: Alan F
authors.initials: AF
authors.lastname: Schatzberg
authors.forename: Edward G
authors.initials: EG
authors.lastname: Jones
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watson
authors.forename: Huda
authors.initials: H
authors.lastname: Akil
authors.forename: William E
authors.initials: WE
authors.lastname: Bunney
mesh_terms: D056930:ARNTL Transcription Factors; D000328:Adult; D000368:Aged; D001344:Autopsy; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D056950:Period Circadian Proteins / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; C107989:BHLHE40 protein, human; C422085:BHLHE41 protein, human; C064353:NR1D1 protein, human
keywords: circadian rhythms; depression; microarray