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

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

doi:10.1073/pnas.1305814110

Cited by 490 publications

(427 citation statements)

References 38 publications

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“…2). Their patterns of expression were strikingly similar across the two brain regions and also to those published previously (24), demonstrating the consistency in the use of these analyses to detect significant rhythms in gene expression in human postmortem tissue. The top 50 genes with significant circadian rhythms in expression are listed in Fig.…”

Section: Resultssupporting

confidence: 80%

“…In the human brain, the investigation of brain region-specific transcriptional rhythms across the life span has been challenging due to the lack of control of environmental factors, such as time of death, sleep-wake cycles, and exposure to other factors known to influence rhythms. A recent study overcame some of these obstacles by ordering postmortem samples around a 24-h clock based on their time of death, essentially reconstructing a pseudotime series by treating each individual sample as an independently sampled data point over one 24-h cycle (24). In 55 healthy controls and 34 patients with major depressive disorder (MDD), they found robust expression rhythms of hundreds of genes in several brain regions in control subjects, with many of these genes displaying significantly disrupted or altered expression rhythms in subjects with MDD.…”

Section: Significancementioning

confidence: 99%

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Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

217

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With aging, significant changes in circadian rhythms occur, including a shift in phase toward a “morning” chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann’s area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.

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Section: Resultssupporting

confidence: 80%

Section: Significancementioning

confidence: 99%

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

217

219

View full text Add to dashboard Cite

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“…30. For further information regarding data collection procedures, please see Li et al (31). Final control and MDD sample sizes can be found in Table 1, and demographics are in Table S3.…”

Section: Methodsmentioning

confidence: 99%

Fibroblast growth factor 9 is a novel modulator of negative affect

Aurbach

Inui

Turner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety-and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.fibroblast growth factor 9 | major depression | anxiety | hippocampus | affect T he neurotrophic hypothesis of major depressive disorder (MDD) posits that the neurobiological basis for mood disorders may be due to the dysregulation of growth factors and their effects on brain circuitry (1, 2). This hypothesis is supported by gene expression profiling experiments in postmortem human brains that implicate the fibroblast growth factor (FGF) family and other neurotrophins in MDD (3, 4). To date, only a few growth factors involved in mood disorders, such as brain-derived neurotrophic factor (BDNF) and FGF2, have been studied extensively.Our laboratory and others have demonstrated that FGF2 is down-regulated in the frontal cortices (3), hippocampus (5), and locus coeruleus (4) in depressed individuals. This consistent decrease in FGF2 expression across regions is striking and underscores the likely importance of FGF2 in mediating affect.Follow-up studies from our laboratory and others have focused on the FGF family and have demonstrated a key role of FGF2 in the control of emotional behavior. Rats exposed to chronic social defeat stress, an animal model recapitulating some aspects of MDD, showed decreased hippocampal FGF2 expression relative to unstressed controls (6), whereas subchronic and chronic administration of FGF2 had antidepressant properties (7,8). Moreover, adminis...

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“…To identify which of the 24 hippocampus modules from patients with TLE had co-expression patterns unrelated to epilepsy, for each module, we compared its co-expression topology in patients with TLE with that from hippocampus samples ascertained from persons with no history of psychiatric or neurological illness 15 . This comparative network analysis was undertaken using the default network dissimilarity measure in WGCNA based on the topological overlap matrix (TOM) 14 .…”

Section: Table 2)mentioning

confidence: 99%

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

et al. 2015

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2Genetic determinants of cognition are poorly characterized and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here, we used a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities including memory. Using exome sequence data from 6,871 trios, we find that M3 genes are also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease genes in the developed human brain, and provide empirical support for a convergent generegulatory network influencing cognition and neurodevelopmental disease.Cognition refers to human mental abilities such as memory, attention, processing speed, reasoning and executive function. Performance on cognitive tasks varies between individuals and is highly heritable 1 and polygenic 2,3 . However, to date, progress in identifying molecular genetic contributions to healthy human cognitive abilities has been limited 4,5 .A distinction can be made between cognitive domains such as the ability to apply acquired knowledge and learned skills (so called crystallized abilities) and fluid cognitive abilities such as the capacity to establish new memories, reason in novel situations or perform cognitive tasks accurately and quickly 6 . Notably, within individuals, performance on different measures of cognitive ability tend to be positively correlated such that people who do well in one domain, such as memory, tend to do well in other domains 7 . Seemingly disparate domains of cognitive ability also show high levels of genetic correlation in twin studies, typically in excess of 0.6 8 , and analyses using genome-wide similarity between unrelated individuals 3 (genome-wide complex trait analysis, GCTA) has also demonstrated substantial genetic correlation between diverse cognitive and learning abilities 9,10 . These studies suggest genes that influence human cognition may exert pleiotropic effects across diverse cognitive domains, such that genes regulating one cognitive ability might influence other cognitive abilities.Since impairment of cognitive function is a core clinical feature of many neurodevelopmental diseases including schizophrenia 11 , autism 12 , epilepsy 13 and intellectual disability (by definition), we sought to investigate gene-regulatory networks for human cognition and to determine their relationship to neurodevelopmental disease. An overview of our experimental design is provided in Supplementary Fig. 1. RESULTS Gene co-expression network a...

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

Cited by 490 publications

References 38 publications

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex

Fibroblast growth factor 9 is a novel modulator of negative affect

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

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