1. ¹Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
2. ²INSERM U513, Université Paris XII, Créteil, France
3. ³Department of Child and Adolescent Psychiatry, Göteborg University, Göteborg, Sweden
4. ⁴Institute of Clinical Sciences, Lund University, Malmö, Sweden
5. ⁵Service de Psychopathologie de l'Enfant et de l'Adolescent, Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
6. ⁶Service de Physiologie-Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil, France
7. ⁷Service de Biochimie, IFR 139, Hôpital Lariboisiére, Assistance Publique-Hôpitaux de Paris, EA 3621, Faculté de Pharmacie, Paris, France
8. ⁸Département de Psychiatrie, Hôpital Henri Mondor et Albert Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, France
9. ⁹Saint George's Hospital Medical School, London, UK
10. ¹⁰University Denis Diderot Paris 7, Paris, France

Correspondence: Professor T Bourgeron, Human Genetics and Cognitive Functions, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France. E-mail: thomasb@pasteur.fr

¹¹Paris Autism Research International Sibpair Study: Sweden, Department of Child and Adolescent Psychiatry, Göteborg University, Göteborg; Christopher Gillberg, Maria Råstam, Carina Gillberg, Gudrun Nygren, Henrik Anckarsäter, Ola Ståhlberg, Catrin Håkansson. France, Department of Psychiatry, Hôpital Albert Chenevier et Henri Mondor, Créteil; Marion Leboyer, INSERM U513, Université Paris XII, Créteil: Catalina Betancur; Service de Psychopathologie de l'Enfant et l'Adolescent, Hôpital Robert Debré, Paris; Pauline Chaste, Richard Delorme, Nadia Chabane, Marie-Christine Mouren-Siméoni; INSERM U679, Hôpital Pitié-Salpêtriére, Paris; Alexis Brice. Norway, Center for Child and Adolescent Psychiatry, University of Oslo, Oslo; Eili Sponheim, Department of Pediatrics, Rikshospitalet, University of Oslo, Oslo; Ola H Skjeldal, USA, Department of Pediatrics, Georgetown University School of Medicine, Washington DC; Mary Coleman, Children's National Medical Center, George Washington University School of Medicine, Washington, DC; Philip L Pearl, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York; Ira L Cohen, John Tsiouris. Italy, Divisione di Neuropsichiatria Infantile, Azienda Ospedaliera Senese, Siena; Michele Zappella. Austria, Department of General Psychiatry, University Hospital, Vienna; Harald Aschauer. Belgium, Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gerpinnes, Loverval; Lionel Van Maldergem.

Received 17 September 2006; Revised 29 March 2007; Accepted 3 April 2007; Published online 15 May 2007.

Abstract

Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 10^-10). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 10^-12) and melatonin level (P=3 10^-11) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.