A polymorphism at the 3′‐untranslated region of the CLOCK gene is associated with adult attention‐deficit hyperactivity disorder

Abstract

Attention-deficit hyperactivity disorder (ADHD) is frequently found in childhood and persists in about 50% of cases into adulthood. Several studies demonstrate a relationship between ADHD, circadian rhythmicity and sleeping disturbances in unmedicated ADHD patients. Since ADHD is a very complex disease with a high genetic load involving multiple genes of moderate effect, we hypothesized a link between adult ADHD and genes involved in the circadian timekeeping system. A 3'-UTR polymorphism of the circadian locomotor output cycles protein kaput (CLOCK) gene, rs1801260, has been linked to disturbed sleep patterns, although both the C-allele and more controversially the T-allele have been proposed as risk factors for different measures of evening preference. This study compared self-rating and interview based measures of ADHD psychopathology of 143 subjects with and without ADHD with their rs1801260 genotype to test the hypothesis that ADHD is linked to one of the alleles of the CLOCK polymorphism. The T > C single nucleotide polymorphism rs1801260 was genotyped in DNA isolated from blood samples. The associations between genotype and ADHD-scores were compared using non-parametric ANCOVA with post hoc pairwise comparisons. There was a strong, significant association (P < 0.001) between each of the adult ADHD assessments and the rs1801260 polymorphism with at least one T-mutation being the risk allele. This is the first study suggesting that a polymorphism of a gene within the circadian "clock" mechanism is a direct or linked contributing factor in adult ADHD.

Methylphenidate Modifies the Motion of the Circadian Clock

“…When examining the subset of ADHD patients with sleep-onset insomnia, additional symptoms are observed, most notably delayed onset and offset of sleep, delayed dim-light melatonin onset, and an attenuated amplitude of the rest-activity cycle (Novakova et al, 2011;Van Veen et al, 2010), all symptoms consistent with a disruption of the circadian clock. Supporting this is the recent observation that a polymorphism associated with the gene clock, one of the molecular 'gears' of the intracellular circadian clock, may be a contributing factor for adult ADHD (Kissling et al, 2008).…”

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

“…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].…”

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

“…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.…”