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Genetic and Functional ascertainment of the Melatonin Pathway in Patients with Attention Deficit and Hyperactivity Disorders
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Sleep wake cycles are frequently disturbed in patients with Attention Deficit and Hyperactivity Disorders. We hypothesized that the origin of the sleep problems may be the consequence of an abnormal circadian clock setting regulated by the melatonin pathway. Here, we sequenced all the genes of the melatonin pathway AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 in 328 individuals from Sweden including 108 patients with ADHD and 220 from the general population. Non-synonymous mutations were identified in all genes at a similar frequency in patients with ADHD and in controls. Among the functional variations, a splice site mutation (IVS5+2T>C) in ASMT and one stop mutation (Y170X) in MTNR1A were only detected in patients with ADHD. Biochemical analyses indicated that these mutations abolish the activity of ASMT and MTNR1A. We also identified clusters of SNPs within MTNR1B showing significant difference in the allelic frequency between ADHD patients and control (maximum signal at rs10830961 P=0.0002). Taken together, these genetic and functional results shed light on one new compelling candidate pathway for susceptibility to circadian rhythms alterations that could help clinicians for providing better treatments of patients with ADHD and sleep problems.
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