Association study between a polymorphism at the 3'-untranslated region of CLOCK gene and attention deficit hyperactivity disorder

Xu, Xiaohui; Breen, Gerome; Chen, Chih‐Ken; Huang, Yu‐Shu; Wu, Yu‐Yu; Asherson, Philip

doi:10.1186/1744-9081-6-48

Cited by 86 publications

(56 citation statements)

References 42 publications

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“…Of note, adult ADHD is linked with blunted Per2 expression (Baird et al, 2012). It is also interesting that the other clock genes with altered circadian profiles in ENT1 KO mice, Clock and Dbp, are associated with ADHD (Kissling et al, 2008;Roybal et al, 2007;Xu et al, 2010), bipolar disorder (Le-Niculescu et al, 2008;Lee et al, 2010;Shi et al, 2008;Soria et al, 2010), anxiety (Le-Niculescu et al, 2011a), and AUD (Le-Niculescu et al, 2011b;Le-Niculescu et al, 2008). Interestingly, ENT1 KO mice display mania-like behavior (Ruby et al, 2011) similar to Dbp KO mice (Le-Niculescu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Ruby

Vadnie

Hinton

et al. 2014

Neuropsychopharmacol

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Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the cooccurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption.

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Section: Discussionmentioning

confidence: 99%

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Ruby

Vadnie

Hinton

et al. 2014

Neuropsychopharmacol

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“…While this provocative finding requires further study, it reinforces the idea that ADHD may involve the circadian clock and/or be related to photic inputs. Candidate gene studies suggest that ADHD and dimensional inattention may be associated with the CLOCK -3111T/C variant genotype [63][64][65]. While clock gene variants are not among the strongest associations with ADHD found by GWAS, clock gene variants may be enriched among weaker GWAS associations [58].…”

Section: Attention Deficit Hyperactivity Disorder (Adhd)mentioning

confidence: 99%

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Landgraf

McCarthy

Welsh

2014

Curr Psychiatry Rep

144

100

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Many psychiatric disorders are characterized by circadian rhythm abnormalities including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Animal models with mutations in circadian "clock genes" commonly show disturbances in reward processing, locomotor activity and novelty seeking behaviors, further supporting the idea of a connection between the circadian clock and psychiatric disorders. However, if circadian clock dysfunction is a common risk factor for multiple psychiatric disorders, it is unknown if and how these putative clock abnormalities could be expressed differently, and contribute to multiple, distinct phenotypes. One possible explanation is that the circadian clock modulates the biological responses to stressful environmental factors that vary with an individual's experience. It is known that the circadian clock and the stress response systems are closely related: Circadian clock genes regulate the physiological sensitivity to, and rhythmic release of glucocorticoids (GC). In turn, GCs have reciprocal effects on the clock. Since stressful life events or increased vulnerability to stress are risk factors for multiple psychiatric disorders including posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), alcohol use disorder (AUD) and schizophrenia (SCZ), we propose that modulation of the stress response is a common mechanism by which circadian clock genes affect these illnesses. Presently, we review how molecular components of the circadian clock may contribute to these six psychiatric disorders, and present the hypothesis that modulation of the stress response may constitute a common mechanism by which the circadian clock affects multiple psychiatric disorders.

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“…13,14 The molecular basis of such circadian rhythm generation consists of positive and negative transcriptional/translational feedback loops of 'clock' genes and their protein products, and single-nucleotide polymorphism in clock genes have been associated with ADHD. [15][16][17] Given these indications that the circadian clock may be compromised in ADHD, we have examined for the first time circadian rhythmicity at the molecular, endocrine and behavioural levels in adult ADHD.…”

Section: Introductionmentioning

confidence: 99%

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

et al. 2011

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Attention-deficit hyperactivity disorder (ADHD) in adults is associated with impaired sleep, and it has been postulated that this impairment may contribute to the psychopathology of this common condition. One key driver of sleep/wake cycles is the circadian system, which at the molecular level consists of a series of transcriptional feedback loops of clock genes, which in turn produce endocrine, physiological and behavioural outputs with a near 24 h periodicity. We set out to examine circadian rhythms at the behavioural, endocrine and molecular levels in ADHD. Adults with ADHD as well as age-and sex-matched controls were recruited. Circadian rhythms were measured by means of actigraphy for the determination of gross motor patterns, by self-sampling of oral mucosa for assessment of rhythmic expression of the clock genes BMAL1 and PER2, and by estimation of salivary cortisol and melatonin levels. Actigraphic analysis revealed significant diurnal and nocturnal hyperactivity in the ADHD group, as well as a significant shorter period of best fit for the locomotor circadian rhythm in ADHD. BMAL1 and PER2 showed circadian rhythmicity in controls with this being lost in the ADHD group. Cortisol rhythms were significantly phase delayed in the ADHD group. These findings indicate that adult ADHD is accompanied by significant changes in the circadian system, which in turn may lead to decreased sleep duration and quality in the condition. Further, modulation of circadian rhythms may represent a novel therapeutic avenue in the management of ADHD.

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Association study between a polymorphism at the 3'-untranslated region of CLOCK gene and attention deficit hyperactivity disorder

Cited by 86 publications

References 42 publications

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels

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