Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder.

Bruno Etain 1, 2 Anne Dumaine 1, 2 Frank Bellivier 3, 1, 2 Cécile Pagan 4, 5, 6, 1 Laetitia Francelle 1, 2 Hany Goubran-Botros 6, 1, 4 Sarah Moreno 6, 1, 4 Jasmine Deshommes 7, 1, 2 Khaled Moustafa 1, 2 Katia Le Dudal 1, 2 Flavie Mathieu 1, 2 Chantal Henry 1, 2, 3 Jean-Pierre Kahn 8, 1 Jean-Marie Launay 1, 5 Thomas Mühleisen 9 Sven Cichon 10, 9 Thomas Bourgeron 6, 1, 4 Marion Leboyer 1, 2, 3 Stéphane Jamain 1, 2, *
* Corresponding author
1 Fondation FondaMental [Créteil]
2 Psychiatrie génétique
3 UPE - Université Paris-Est
4 Gènes, Synapses et Cognition
5 Hôpital Lariboisière
6 Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions
7 CIC - CHU Henri Mondor
8 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
9 University of Bonn
10 Research Center Juelich
Abstract : Patients affected by bipolar disorder (BD) frequently report abnormalities in sleep/wake cycles. In addition, they showed abnormal oscillating melatonin secretion, a key regulator of circadian rhythms and sleep patterns. The acetylserotonin O-methyltransferase (ASMT) is a key enzyme of the melatonin biosynthesis and has recently been associated with psychiatric disorders such as autism spectrum disorders and depression. In this paper, we analysed rare and common variants of ASMT in patients with BD and unaffected control subjects and performed functional analysis of these variants by assaying the ASMT activity in their B-lymphoblastoid cell lines. We sequenced the coding and the regulatory regions of the gene in a discovery sample of 345 patients with BD and 220 controls. We performed an association study on this discovery sample using common variants located in the promoter region and showed that rs4446909 was significantly associated with BD (P= 0.01) and associated with a lower mRNA level (P< 10(-4)) and a lower enzymatic activity (P< 0.05) of ASMT. A replication study and a meta-analysis using 480 independent patients with BD and 672 controls confirmed the significant association between rs4446909 and BD (P= 0.002). These results correlate with the general lower ASMT enzymatic activity observed in patients with BD (P= 0.001) compared with controls. Finally, several deleterious ASMT mutations identified in patients were associated with low ASMT activity (P= 0.01). In this study, we determined how rare and common variations in ASMT might play a role in BD vulnerability and suggest a general role of melatonin as susceptibility factor for BD.
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Submitted on : Friday, September 1, 2017 - 10:19:15 AM
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Bruno Etain, Anne Dumaine, Frank Bellivier, Cécile Pagan, Laetitia Francelle, et al.. Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder.. Human Molecular Genetics, Oxford University Press (OUP), 2012, 21 (18), pp.4030-7. ⟨10.1093/hmg/dds227⟩. ⟨pasteur-01580143⟩

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