Cited by 589Circadian rhythm and melatoninTreatment of Major DepressionSleep and Wakefulness Research

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

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Li, Jun Z., Bunney, Blynn G., Meng, Fan, Hagenauer, Megan H., Walsh, David M., Vawter, Marquis P., Evans, Simon J., Choudary, Prabhakara V., Cartagena, Preston, Barchas, Jack D., Schatzberg, Alan F., Jones, Edward G., Myers, Richard M., Watson, Stanley J., Akil, Huda, Bunney, William E.·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1305814110PMC PMC3683716

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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.

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Self-citation
Circadian neurogenetics of mood disorders
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Authors: 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.
Affiliations: University of Michigan (US)
University of California, Irvine (US)
University of California, Davis (US)
Weill Cornell Medicine (US)
Stanford University (US)
HudsonAlpha Institute for Biotechnology (US)
ORCID: Li, Jun Z.
Bunney, Blynn G.
Meng, Fan
Hagenauer, Megan H.
Walsh, David M.
Vawter, Marquis P.
Evans, Simon J.
Choudary, Prabhakara V.
Barchas, Jack D.
Schatzberg, Alan F.
Jones, Edward G.
Myers, Richard M.
Watson, Stanley J.
Akil, Huda
Bunney, William E.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-05-13
Volume: 110
Issue: 24
Pages: 9950-9955
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1305814110
PMC: PMC3683716
OpenAlex: W2027764072
Cited by: 589
References: 59
Citations by year: 2026: 26 · 2025: 37 · 2024: 44 · 2023: 39 · 2022: 52 · 2021: 54 · 2020: 60 · 2019: 49 · 2018: 49 · 2017: 48 · 2016: 35 · 2015: 52 · 2014: 35 · 2013: 9
FWCI: 23.61
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: other-oa
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Public Health Service (NIMH R01MH085801)
National Institute of Mental Health (P50MH60398, R01MH085801, P50MH060398)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
Keywords: major depressive disorder, circadian rhythm, clock genes, gene expression rhythms, human brain transcriptome, postmortem brain, dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, cerebellum, Bmal1, per gene, DBP, BHLHE40, BHLHE41, mood disorders
MeSH terms: Adult, Aged, Autopsy, Brain, Circadian Rhythm, Major Depressive Disorder, Female, Humans, Male, Middle Aged, Homeodomain Proteins, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Basic Helix-Loop-Helix Proteins, ARNTL Transcription Factors, Period Circadian Proteins, Nuclear Receptor Subfamily 1, Group D, Member 1, Circadian Clocks

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

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