Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders: The melatonin pathway in ADHD
Abstract
Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.
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Coding mutations in the melatonin biosynthesis pathway were found in a sample of 101 adults with ADHD.
“Chaste et al. (2011) report the presence of coding mutations in the melatonin biosynthesis pathway found in a sample of 101 adults with ADHD”
From A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder (2017) · cites this paper as Chaste et al. (2011)
Coding mutations in the melatonin biosynthesis pathway were not significantly enriched compared to the control population in adults with ADHD.
“but these mutations were not significantly enriched compared to the control population.”
From A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder (2017) · cites this paper as Chaste et al. (2011)
Cites
Diagnostic and Statistical Manual of Mental Disorders
(2018) · Sage eBooks · doi:10.4135/9781506326139.n198 · Cited by 1,243 · see citing works
Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia.
Weiss, M. D., Wasdell, M. B., Bomben, M. M., Rea, K., & Fréeman, R. D. (2006) · PubMed · doi:10.1097/01chi.0000205706.78818.ef · Cited by 1,213 · see citing works
Simonneaux, V., & Ribelayga, C. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.2.2 · Cited by 740 · see citing works
The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood
Lichtenstein, P., Carlström, E., Råstam, M., Gillberg, C., & Anckarsäter, H. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.10020223 · Cited by 738 · see citing works
Self-citationKonrad, K., & Eickhoff, S. B. (2010) · Human Brain Mapping · doi:10.1002/hbm.21058 · Cited by 670 · see citing works
Melatonin: A Multitasking Molecule
Reiter, R. J., Tan, D. X., & Fuentes‐Broto, L. (2010) · Progress in brain research · doi:10.1016/s0079-6123(08)81008-4 · Cited by 642 · see citing works
Williams, N. M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., Gudmundsson, O. O., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)61109-9 · Cited by 572 · see citing works
Abnormal melatonin synthesis in autism spectrum disorders
Melke, J., Goubran Botros, H., Chaste, P., Betancur, C., Nygren, G., Anckarsäter, H., Rastam, M., Ståhlberg, O., Gillberg, I. C., Delorme, R., et al. (2008) · Molecular Psychiatry · doi:10.1038/sj.mp.4002016 · Cited by 511 · see citing works
Self-citationGenome-wide association studies in ADHD
Franke, B., Neale, B., & Faraone, S. (2009) · Human Genetics · doi:10.1007/s00439-009-0663-4 · Cited by 462 · see citing works
Effect of Melatonin on Sleep, Behavior, and Cognition in ADHD and Chronic Sleep-Onset Insomnia
VAN der HEIJDEN, K. B., SMITS, M. G., VAN SOMEREN, E. J. W., RIDDERINKHOF, K. R., & GUNNING, W. B. (2007) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/01.chi.0000246055.76167.0d · Cited by 378 · see citing works
Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease
Paradies, G., Petrosillo, G., Paradies, V., Reiter, R. J., & Ruggiero, F. M. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00759.x · Cited by 378 · see citing works
Levoye, A., Dam, J., Ayoub, M. A., Guillaume, J., Couturier, C., Delagrange, P., & Jockers, R. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601193 · Cited by 335 · see citing works
Self-citationKey role for gene dosage and synaptic homeostasis in autism spectrum disorders
Toro, R., Konyukh, M., Delorme, R., Leblond, C., Chaste, P., Fauchereau, F., Coleman, M., Leboyer, M., Gillberg, C., & Bourgeron, T. (2010) · Trends in Genetics · doi:10.1016/j.tig.2010.05.007 · Cited by 331 · see citing works
Self-citationAyoub, M. A., Couturier, C., Lucas-Meunier, E., Angers, S., Fossier, P., Bouvier, M., & Jockers, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200729200 · Cited by 322 · see citing works
Self-citationVan Veen, M. M., Kooij, J. J. S., Boonstra, A. M., Gordijn, M. C. M., & Van Someren, E. J. W. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.12.032 · Cited by 300 · cited 1× · see citing works
“Alteration in sleep is notably frequent in patients with ADHD, and low melatonin levels as well as an abnormal delay of melatonin onset was reported in patients with ADHD and chronic sleep onset insomnia [4–6].”
BackgroundMelatonin receptors, heterodimerization, signal transduction and binding sites: what's new?
Jockers, R., Maurice, P., Boutin, J. A., & Delagrange, P. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.184 · Cited by 293 · see citing works
Self-citationVan der Heijden, K. B., Smits, M. G., Someren, E. J. W. V., & Boudewijn Gunning, W. (2005) · Chronobiology International · doi:10.1081/cbi-200062410 · Cited by 269 · see citing works
Long‐term follow‐up of melatonin treatment in children with ADHD and chronic sleep onset insomnia
Hoebert, M., Van Der Heijden, K. B., Van Geijlswijk, I. M., & Smits, M. G. (2009) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2009.00681.x · Cited by 220 · see citing works
The mammalian pineal gland: known facts, unknown facets
Maronde, E., & Stehle, J. H. (2007) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2007.03.001 · Cited by 178 · see citing works
Léger, D., Laudon, M., & Zisapel, N. (2004) · The American Journal of Medicine · doi:10.1016/j.amjmed.2003.07.017 · Cited by 157 · see citing works
Jung, K. H., Hong, S., Zheng, H., Lee, H., Lee, D., Lee, D., Lee, S. Y., & Hong, S. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00748.x · Cited by 150 · see citing works
Melatonin Treatment for Insomnia in Pediatric Patients with Attention-Deficit/Hyperactivity Disorder
Bendz, L. M., & Scates, A. C. (2010) · Annals of Pharmacotherapy · doi:10.1345/aph.1m365 · Cited by 114 · cited 1× · see citing works
“In addition, the sleep of patients with ADHD is greatly improved by the use of melatonin as a medication [8–12], suggesting that the endogenous level of melatonin is not sufficient to reset the biologic clock.”
BackgroundMutation screening of melatonin-related genes in patients with autism spectrum disorders
Jönsson, L., Ljunggren, E., Bremer, A., Pedersen, C. T., Landén, M., Thuresson, K., Giacobini, M., & Melke, J. (2010) · BMC Medical Genomics · doi:10.1186/1755-8794-3-10 · Cited by 113 · see citing works
Self-citationAdvances in genetic findings on attention deficit hyperactivity disorder
Thapar, A., Langley, K., Owen, M. J., & O’Donovan, M. C. (2007) · Psychological Medicine · doi:10.1017/s0033291707000773 · Cited by 106 · see citing works
Chaste, P., Clément, N., Mercati, O., Guillaume, J., Delorme, R., Goubran‐Botros, H., Pagan, C., Périvier, S., Scheid, I., Nygren, G., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011495 · Cited by 103 · see citing works
Self-citationCai, G., Edelmann, L. J., Goldsmith, J., Cohen, N., Nakamine, A., Reichert, J. G., Hoffman, E. J., Zurawiecki, D., Silverman, J. M., Hollander, E., et al. (2008) · BMC Medical Genomics · doi:10.1186/1755-8794-1-50 · Cited by 94 · see citing works
Tjon Pian Gi, C. V., Broeren, J. P. A., Starreveld, J. S., & A. Versteegh, F. G. (2003) · European Journal of Pediatrics · doi:10.1007/s00431-003-1207-x · Cited by 85 · cited 1× · see citing works
“In addition, the sleep of patients with ADHD is greatly improved by the use of melatonin as a medication [8–12], suggesting that the endogenous level of melatonin is not sufficient to reset the biologic clock.”
BackgroundGałecki, P., Szemraj, J., Bartosz, G., Bieńkiewicz, M., Gałecka, E., Florkowski, A., Lewiñski, A., & Karbownik‐Lewińska, M. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00754.x · Cited by 64 · see citing works
Halmøy, A., Johansson, S., Winge, I., McKinney, J. A., Knappskog, P. M., & Haavik, J. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.124 · Cited by 56 · see citing works
Claudio Toma, A., Rossi, M., Sousa, I., Blasi, F., Bacchelli, E., Alén, R., Vanhala, R., Monaco, A. P., Järvelä, I. E., & Maestrini, E. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4002069 · Cited by 50 · see citing works
Jarzynka, M. J., Passey, D. K., Johnson, D. A., Konduru, N. V., Fitz, N. F., Radio, N. M., Rasenick, M. M., Benloucif, S., Melan, M. A., & Witt‐Enderby, P. A. (2009) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2008.00644.x · Cited by 39 · see citing works
Chae, H., Park, T., Lee, Y., et al. (1999) · Neurochemistry International · doi:10.1016/s0197-0186(99)00086-8 · Cited by 32 · see citing works
Soliva, J. C., Carmona, S., Fauquet, J., Hoekzema, E. A., Bulbena, A., Hilferty, J., & Vilarroya, Ó. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04604.x · Cited by 25 · see citing works
Laakso, M., Lindblom, N., Leinonen, L. M., & Kaski, M. (2007) · Sleep Medicine · doi:10.1016/j.sleep.2006.09.006 · Cited by 22 · see citing works
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Hardeland, R. (2018) · Journal of Pineal Research · doi:10.1111/jpi.12525 · Cited by 455 · see citing works
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Reiter, R. J., Tan, D. X., Korkmaz, A., & Rosales-Corral, S. A. (2014) · Human Reproduction Update · doi:10.1093/humupd/dmt054 · Cited by 371 · see citing works
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Karamitri, A., & Jockers, R. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0130-1 · Cited by 268 · see citing works
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Zheng, F., Gao, P., He, M., Li, M., Wang, C., Zeng, Q., Zhou, Z., Yu, Z., & Zhang, L. (2014) · BMC Public Health · doi:10.1186/1471-2458-14-1022 · Cited by 113 · see citing works
“[DSM-IV-TR]) [25-27].”
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Liu, L., Labani, N., Cecon, E., & Jockers, R. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00791 · Cited by 102 · see citing works
Self-citationBralten, J., Franke, B., Waldman, I., Rommelse, N., Hartman, C., Asherson, P., Banaschewski, T., Ebstein, R. P., Gill, M., Miranda, A., et al. (2013) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2013.08.020 · Cited by 93 · see citing works
Arns, M., van der Heijden, K. B., Arnold, L. E., & Kenemans, J. L. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.010 · Cited by 93 · see citing works
Molina-Carballo, A., Naranjo-Gómez, A., Uberos, J., Justicia-Martínez, F., Ruiz-Ramos, M.-J., Cubero-Millán, I., Contreras-Chova, F., Augustin-Morales, M.-D.-C., Khaldy-Belkadi, H., & Muñoz-Hoyos, A. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.09.020 · Cited by 43 · see citing works
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- Authors
- Chaste, P., Clement, N., Botros, H. G., Guillaume, J.-L., Konyukh, M., Pagan, C., Scheid, I., Nygren, G., Anckarsäter, H., Rastam, M., Ståhlberg, O., Gillberg, I. C., Melke, J., Delorme, R., Leblond, C., Toro, R., Huguet, G., Fauchereau, F., Durand, C., Boudarene, L., Serrano, E., Lemière, N., Launay, J. M., Leboyer, M., Jockers, R., Gillberg, C., & Bourgeron, T.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of Gothenburg (SE)
- Lund University (SE)
- Institut Pasteur (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Inserm (FR)
- St George's Hospital (GB)
- Corresponding author
- Bourgeron, Thomas
- ORCID
- Venue
- Journal of Pineal Research
- Publisher
- Wiley
- Published
- 2011-05-26
- Volume
- 51
- Issue
- 4
- Pages
- 394-399
- ISSN
- 0742-3098 (ISSN-L)
- OpenAlex
- W2170669107
- Cited by
- 67
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 10 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 13 · 2013: 7 · 2012: 8
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pineal Research (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Keywords
- attention deficit hyperactivity disorder, genetic variation, ASMT, MTNR1A, MTNR1B, GPR50, splice site mutation
- MeSH terms
- Acetylserotonin O-Methyltransferase, Attention Deficit Disorder with Hyperactivity, Female, Humans, Male, Melatonin, Nerve Tissue Proteins, Genetic Variation, Receptors, G-Protein-Coupled, Receptor, Melatonin, MT1, Arylalkylamine N-Acetyltransferase
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