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

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.