Genetic analysis reveals role of melatonin in ADHD symptom severity

New research published in Psychiatry Research Communications suggests that the hormone melatonin may be closely linked to the severity of attention deficit hyperactivity disorder (ADHD) symptoms in children. A study led by Hamamatsu University School of Medicine found that genetic variations affecting melatonin production could contribute to ADHD symptoms, particularly through disrupted sleep patterns. These findings highlight the potential benefits of healthy sleep routines in managing ADHD symptoms.

Melatonin is a hormone naturally produced by the pineal gland in response to darkness, helping regulate sleep-wake cycles. It signals the body when it’s time to sleep, supporting our internal “biological clock,” or circadian rhythm. Disruptions in melatonin production can make it harder to fall asleep, affecting sleep quality and overall well-being. Melatonin has other roles as well, including supporting immune function and reducing inflammation.

For many individuals, melatonin secretion follows a predictable pattern, rising in the evening and lowering in the morning. However, this pattern can vary, and certain conditions may interfere with typical melatonin levels, disrupting the sleep cycle.

ADHD, a neurodevelopmental disorder, is characterized by symptoms of inattention, hyperactivity, and impulsivity. For children with ADHD, one common challenge is establishing a stable sleep routine. Many struggle to fall asleep on time, which worsens their daytime symptoms and leads to a cycle of sleep deprivation and increased hyperactivity or inattention.

While ADHD’s exact causes are complex, involving genetic, neurological, and environmental factors, recent research suggests that sleep disruptions could be a contributing factor. Specifically, children with ADHD often exhibit delayed melatonin secretion, which might be linked to difficulties in winding down and falling asleep at night.

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“Sleep disturbances are common in children with ADHD, yet the mechanisms are not fully understood. Our interest stemmed from the hypothesis that disrupted melatonin secretion, a key regulator of circadian rhythms, may play a role in ADHD, potentially linking sleep patterns with genetic risk factors,” said study author Nagahide Takahashi, who is now a director in the Department of Neurodevelopmental Disorders at the National Center of Neurology and Psychiatry in Tokyo.

To investigate this, the researchers gathered and analyzed genetic data from three large cohorts: the Lundbeck Foundation’s Initiative for Integrative Psychiatric Research, the Taiwan Biobank, and the Hamamatsu Birth Cohort for Mothers and Children. These groups combined data from 27,076 individuals from the first cohort, 2,373 from the second, and 726 from the third.

The study analyzed melatonin levels indirectly by measuring a metabolite called 6-hydroxymelatonin sulfate, which is excreted in urine and serves as a practical substitute for measuring melatonin directly. Levels of this metabolite, adjusted for creatinine to account for urine concentration differences, were used to determine the urine metabolite-to-creatinine ratio (UMCR), a proxy measure of melatonin secretion.

The researchers then conducted a genetic correlation analysis using genome-wide association study summary data from these cohorts. They constructed a polygenic risk score based on the UMCR to assess whether genetic variations linked to melatonin secretion correlated with ADHD symptoms. They also performed additional analyses to explore the relationship between melatonin secretion, sleep behaviors, and ADHD, including examining pathways that might connect melatonin with immune responses in ADHD, particularly focusing on the role of interleukin-6, a molecule known to be involved in neuroinflammation.

The results revealed a significant correlation between genetic markers associated with melatonin secretion and ADHD symptoms in children. This association was most notable for ADHD symptoms related to inattention, suggesting that children with these symptoms might be more prone to circadian rhythm disturbances linked to lower melatonin levels.

The researchers found that children with higher UMCR-based risk scores for reduced melatonin secretion tended to have more severe ADHD symptoms. Although the study showed a genetic link between melatonin production and ADHD, the researchers did not find that sleep onset delay alone explained this relationship. Instead, they proposed that both ADHD symptoms and disrupted melatonin secretion could stem from a shared genetic predisposition.

“It was surprising to find that while genetic factors influencing melatonin secretion correlated with ADHD symptoms, sleep onset delays did not mediate this relationship, suggesting a more direct genetic influence,” Takahashi told PsyPost.

The pathway-based analysis provided additional insights into the biological mechanisms that might connect melatonin and ADHD symptoms. The team found that several pathways involving interleukin-6 were significantly associated with both melatonin secretion and ADHD symptoms. Interleukin-6, a molecule linked with inflammation, has been observed at elevated levels in children with ADHD, and the researchers found that this pathway could be involved in the link between melatonin and ADHD.

These findings suggest that the interaction between sleep disturbances and ADHD symptoms may be biologically rooted. The researchers proposed that encouraging healthy sleep habits that increase melatonin production in children with ADHD could help lessen symptoms by potentially reducing levels of interleukin-6.

“Good sleep hygiene and promoting healthy sleep habits in children can potentially mitigate ADHD symptoms,” Takahashi said. “This research highlights the genetic link between melatonin secretion and ADHD, emphasizing the importance of addressing sleep-related factors in managing ADHD.”

Despite these significant findings, the study had limitations. The researchers did not have access to direct melatonin measurements in the children’s blood or urine, which could have strengthened the results.

Future research could explore the therapeutic potential of melatonin regulation to support children with ADHD. This might include interventions that promote circadian rhythm alignment, such as scheduled sleep routines or even low-dose melatonin supplements. Further studies are also planned to investigate how genes, sleep patterns, and ADHD symptoms interact over time.

“We aim to explore how melatonin regulation can be harnessed therapeutically, including the potential use of melatonin supplements or interventions to support circadian rhythm alignment in children with ADHD,” Takahashi said.

“This study emphasizes the intersection of genetics, sleep, and behavior. Collaborative research combining genetic, clinical, and lifestyle interventions can pave the way for holistic ADHD management,” he added.

The study, “Association between genetic risk of melatonin secretion and attention deficit hyperactivity disorder,” was authored by Nagahide Takahashi, Tomoko Nishimura, Akemi Okumura, Taeko Harada, Toshiki Iwabuchi, Md. Shafiur Rahman, Pi-Hua Liu, Gwo-Tsann Chuang, Yi-Cheng Chang, Yoko Nomura, and Kenji J. Tsuchiya.