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Circadian patterns of gene expression in the human brain and disruption in major depressive disorder
Open accessAbstract
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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“Notably, neural systems associated with affect, such as the limbic brain regions, monoamine neurotransmitters, and the hypothalamic–pituitary–adrenal axis (HPA), are all under circadian regulation27–31.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [27]
In the citing paper
“Further, examination of circadian patterns of gene expression within postmortem brains of patients with MDD demonstrate reduced amplitude, shifted peaks, and altered phase relationship between genes, particularly in canonical clock genes27.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [27]
Citations
Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,893
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603
Adjusting batch effects in microarray expression data using empirical Bayes methods
Johnson, W. E., Li, C., & Rabinovic, A. (2007) · Biostatistics · doi:10.1093/biostatistics/kxj037 · Cited by 8,658
Bolstad, B. M., Irizarry, R. A., Åstrand, M., & Speed, T. P. (2003) · Bioinformatics · doi:10.1093/bioinformatics/19.2.185 · Cited by 8,328
Summaries of Affymetrix GeneChip probe level data
Irizarry, R. A. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng015 · Cited by 4,837
Genomic Control for Association Studies
Devlin, B., & Roeder, K. (1999) · Biometrics · doi:10.1111/j.0006-341x.1999.00997.x · Cited by 3,162 · cited 2×
“This artifact is analogous to the phenomenon of population stratification in genetic association studies; thus, we adopted a correction method similar to the genomic control method (17).”
BackgroundMethodMolecular Bases for Circadian Clocks
Dunlap, J. C. (1999) · Cell · doi:10.1016/s0092-8674(00)80566-8 · Cited by 2,900
KEGG for representation and analysis of molecular networks involving diseases and drugs
Kanehisa, M., Goto, S., Furumichi, M., Tanabe, M., & Hirakawa, M. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkp896 · Cited by 2,322
Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock
Panda, S., Antoch, M. P., Miller, B. H., Su, A. I., Schook, A. C., Straume, M., Schultz, P. G., Kay, S. A., Takahashi, J. S., & Hogenesch, J. B. (2002) · Cell · doi:10.1016/s0092-8674(02)00722-5 · Cited by 2,310
Resetting central and peripheral circadian oscillators in transgenic rats
Yamazaki, S., Numano, R., Abe, M., Hida, A., Takahashi, R.-I., Ueda, M., Block, G. D., Sakaki, Y., Menaker, M., & Tei, H. (2000) · Science · doi:10.1126/science.288.5466.682 · Cited by 1,907
Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data
Dai, M. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni179 · Cited by 1,807
The genetics of mammalian circadian order and disorder: implications for physiology and disease
Takahashi, J. S., Hong, H.-K., Ko, C. H., & McDearmon, E. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2430 · Cited by 1,611
Mania-like behavior induced by disruption of CLOCK
Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S. J., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609625104 · Cited by 803
Akhtar, R. A., Reddy, A. B., Maywood, E. S., Clayton, J. D., King, V. M., Smith, A. G., Gant, T. W., Hastings, M. H., & Kyriacou, C. P. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00759-5 · Cited by 777
Harmonics of Circadian Gene Transcription in Mammals
Hughes, M. E., DiTacchio, L., Hayes, K. R., Vollmers, C., Pulivarthy, S. R., Baggs, J. E., Panda, S., & Hogenesch, J. B. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000442 · Cited by 689
Chronobiology: biological timekeeping
(2004) · Choice Reviews Online · doi:10.5860/choice.41-2795 · Cited by 679
The human circadian clock entrains to sun time
Roenneberg, T., Kumar, C., & Merrow, M. W. (2007) · Current Biology · doi:10.1016/j.cub.2006.12.011 · Cited by 464
The Protein Information Resource
Wu, C. H. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg040 · Cited by 455
Clocks not winding down: unravelling circadian networks
Zhang, E. E., & Kay, S. A. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2995 · Cited by 446
REM latency: a psychobiologic marker for primary depressive disease.
Dj, K. (1976) · PubMed · Cited by 443
Vanselow, K., Vanselow, J. T., Westermark, P. O., Reischl, S., Maier, B., Korte, T., Herrmann, A., Herzel, H., Schlösser, A., & Kramer, A. (2006) · Genes & Development · doi:10.1101/gad.397006 · Cited by 387
The Role of Hypocretins (Orexins) in Sleep Regulation and Narcolepsy
Taheri, S., Zeitzer, J. M., & Mignot, E. J.-M. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142826 · Cited by 333
Tomita, H., Vawter, M. P., Walsh, D. M., Evans, S. J., Choudary, P. V., Li, J., Overman, K. M., Atz, M. E., Myers, R. M., Jones, E. G., et al. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2003.10.013 · Cited by 331
Self-citationSpitz, W. U., Spitz, D. J., & Fisher, R. S. (2005) · Medical Entomology and Zoology · Cited by 324
The Period Length of Fibroblast Circadian Gene Expression Varies Widely among Human Individuals
Brown, S. A., Fleury-Olela, F., Nagoshi, E., Hauser, C., Juge-Aubry, C. E., Meier, C. A., Chicheportiche, R., Dayer, J., Albrecht, U., & Schibler, U. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030338 · Cited by 315
Analysis of Gene Regulatory Networks in the Mammalian Circadian Rhythm
Yan, J., Wang, H., Liu, Y., & Shao, C. (2008) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000193 · Cited by 305
Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression
Partonen, T., Treutlein, J., Alpman, A., Frank, J., Johansson, C. H., Depner, M., Aron, L., Rietschel, M., Wellek, S., Soronen, P., et al. (2007) · Annals of Medicine · doi:10.1080/07853890701278795 · Cited by 265
Li, J. Z., Vawter, M. P., Walsh, D. M., Tomita, H., Evans, S. J., Choudary, P. V., Lopez, J. F., Avelar, A., Shokoohi, V., Chung, T., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh065 · Cited by 261
Self-citationMammalian circadian clock and metabolism – the epigenetic link
Bellet, M. M., & Sassone‐Corsi, P. (2010) · Journal of Cell Science · doi:10.1242/jcs.051649 · Cited by 240
A light‐independent oscillatory gene mPer3 in mouse SCN and OVLT
Takumi, T., Taguchi, K., Miyake, S., Sakakida, Y., Takashima, N., Matsubara, C., Maebayashi, Y., Okumura, K., Takekida, S., Yamamoto, S., et al. (1998) · The EMBO Journal · doi:10.1093/emboj/17.16.4753 · Cited by 236
Regulation of metabolism: the circadian clock dictates the time
Sahar, S., & Sassone-Corsi, P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.10.005 · Cited by 222
Gender-Specific Gene Expression in Post-Mortem Human Brain: Localization to Sex Chromosomes
Vawter, M. P., Evans, S. J., Choudary, P. V., Tomita, H., Meador-Woodruff, J., Molnar, M., Li, J. Z., López, J. F., Myers, R. M., Cox, D. R., et al. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300337 · Cited by 204
Self-citationNoninvasive method for assessing the human circadian clock using hair follicle cells
Akashi, M., Soma, H., Yamamoto, T., Tsugitomi, A., Yamashita, S., Yamamoto, T., Nishida, E., Yasuda, A., Liao, J. K., & Node, K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003878107 · Cited by 196
Sartor, M. A., Leikauf, G. D., & Medvedovic, M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn592 · Cited by 178
Wu, Y., Fischer, D. F., Kalsbeek, A., Garidou, M., van der Vliet, J., Heijningen, C. L. V., Liu, R., Zhou, J., & Swaab, D. F. (2006) · The FASEB Journal · doi:10.1096/fj.05-4446fje · Cited by 176
Cermakian, N., Waddington Lamont, E., Boudreau, P., & Boivin, D. B. (2011) · Journal of Biological Rhythms · doi:10.1177/0748730410395732 · Cited by 175
Circadian rhythms and depression: Human psychopathology and animal models
Kronfeld-Schor, N., & Einat, H. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.020 · Cited by 166
Plasticity and specificity of the circadian epigenome
Masri, S., & Sassone‐Corsi, P. (2010) · Nature Neuroscience · doi:10.1038/nn.2668 · Cited by 138
Caldelas, I., Poirel, V.-J., Sicard, B., Pévet, P., & Challet, É. (2003) · Neuroscience · doi:10.1016/s0306-4522(02)00654-1 · Cited by 131
Mrosovsky, N., Edelstein, K., Hastings, M. H., & Maywood, E. S. (2001) · Journal of Biological Rhythms · doi:10.1177/074873001129002141 · Cited by 109
Proof-by-synthesis of the transcriptional logic of mammalian circadian clocks
Ukai‐Tadenuma, M., Kasukawa, T., & Ueda, H. R. (2008) · Nature Cell Biology · doi:10.1038/ncb1775 · Cited by 103
Shedden, K., & Cooper, S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.062569899 · Cited by 103
Oxysterols: Novel biologic roles for the 21st century
Javitt, N. B. (2007) · Steroids · doi:10.1016/j.steroids.2007.10.004 · Cited by 94
Experiences with a compound method for estimating the time since death
Henssge, C., Althaus, L. G., Bolt, J., Freislederer, A., Haffner, H. T., Henssge, C., Hoppe, B., & Schneider, V. (2000) · International Journal of Legal Medicine · doi:10.1007/s004149900090 · Cited by 93
Jiang, W., Li, S., Zhou, S., Sun, Y., Shi, J., & Lü, L. (2011) · Brain Research · doi:10.1016/j.brainres.2011.05.001 · Cited by 85
Sleep and manipulations of the sleep–wake rhythm in depression
Berger, M., Van Calker, D., & Riemann, D. (2003) · Acta Psychiatrica Scandinavica · doi:10.1034/j.1600-0447.108.s418.17.x · Cited by 82
Rapid-acting antidepressant strategies: mechanisms of action
Bunney, B. G., & Bunney, W. E. (2012) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000927 · Cited by 79
Self-citationKaliszan, M., Häuser, R., & Kernbach‐Wighton, G. (2009) · Legal Medicine · doi:10.1016/j.legalmed.2008.12.002 · Cited by 77
Fisher, M., & Spitz, W. U. (1973) · Medical Entomology and Zoology · Cited by 65
Mendlewicz, J., & Kerkhofs, M. (1991) · The British Journal of Psychiatry · doi:10.1192/bjp.159.4.505 · Cited by 62
Phenotypic effects of the circadian gene Cryptochrome 2 on cancer-related pathways
Hoffman, A. E., Zheng, T., Ba, Y., Stevens, R. G., Yi, C., Leaderer, D., & Zhu, Y. L. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-110 · Cited by 60
Evans, S. J., Choudary, P. V., Vawter, M. P., Li, J., Meador‐Woodruff, J. H., López, J. F., Burke, S., Thompson, R. C., Myers, R., Jones, E. G., et al. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00126-8 · Cited by 52
Self-citationThe negative transcription factor E4BP4 is associated with circadian clock protein PERIOD2
Ohno, T., Onishi, Y., & Ishida, N. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.01.084 · Cited by 47
Vosko, A. M., Hagenauer, M. H., Hummer, D. L., & Lee, T. M. (2008) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90392.2008 · Cited by 45
Self-citationCircadian Expression of Clock- and Tumor Suppressor Genes in Human Oral Mucosa
Zieker, D., Jenne, I., Koenigsrainer, I., Zdichavsky, M., Nieselt, K., Buck, K., Zieker, J., Beckert, S., Glatzle, J., Spanagel, R., et al. (2010) · Cellular Physiology and Biochemistry · doi:10.1159/000320547 · Cited by 44
Yang, S., Wang, K., Valladares, O., Hannenhalli, S. S., & Bućan, M. (2007) · Genome biology · doi:10.1186/gb-2007-8-11-r247 · Cited by 42
Day–night expression patterns of clock genes in the human pineal gland
Ackermann, K., Dehghani, F., Bux, R., Kauert, G. F., & Stehle, J. H. (2007) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2007.00461.x · Cited by 26
Sample matching by inferred agonal stress in gene expression analyses of the brain
Li, J. Z., Meng, F., Tsavaler, L., Evans, S. J., Choudary, P. V., Tomita, H., Vawter, M. P., Walsh, D. M. A., Shokoohi, V., Chung, T. R., et al. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-336 · Cited by 19
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“Thus, while the circadian expression signature of the control brain can pinpoint the time of death within an hour of its actual occurrence, the pattern in depressed brains is time shifted, making it impossible to match the circadian signature of the brain with the time of death (Li et al., 2013; Bunney et al., 2015).”
BackgroundSelf-citation
Metadata
- 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
- 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
- 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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