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A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

Molecular Psychiatry volume 15, pages 748–755 (2010)Cite this article

Abstract

Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Early-onset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case–control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

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Acknowledgements

This work was supported by INSERM (Poste d’Accueil INSERM to BE), the National Alliance for Research on Schizophrenia and Affective Disorders (2004 Independent Investigator Award to FB), Assistance Publique des Hôpitaux de Paris, Agence Nationale pour la Recherche (ANR NEURO2006 – Project MANAGE_BPAD), Fondation pour la Recherche sur le Cerveau and Réseau Thématique de Recherche et de Soins en Santé Mentale (Fondation FondaMental). We thank bipolar patients and controls for their participation. Brain specimens were donated by The Stanley Medical Research Institute Brain Collection courtesy of Dr Michael B Knable, Dr E Fuller Torrey, Dr Maree J Webster and Dr Robert H Yolken. We thank MJ Pereira Gomes, E Abadie, A Philippe, the Cochin Hospital cell library (Dr J Chelly), the Clinical Investigation Centre (CIC) of Mondor Hospital (Dr O Montagne and Dr B Ghaleh) and blood donor centre (Dr JL Beaumont and Dr B Mignen, EFS, Créteil) for technical assistance. We thank B Cochet, O Elgrabli, A Raust and L Zanouy for their participation in the clinical evaluation of patients. We thank Professor D Kupfer for helpful discussion and comments on the article.

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Authors and Affiliations

  1. Department of Genetics, INSERM, U 955, IMRB, Psychiatry Genetics, Creteil, F-94010, France,

    B Etain, A Dumaine, F Mathieu, F Chevalier, C Henry, J Deshommes, F Bellivier, M Leboyer & S Jamain

  2. Department of Psychiatry, AP-HP, Henri Mondor-Albert Chenevier Group, Creteil, F-94010, France

    B Etain, C Henry, J Deshommes, F Bellivier & M Leboyer

  3. University Paris 12, Faculty of Medicine, Creteil, F-94010, France,

    C Henry, F Bellivier & M Leboyer

  4. Department of Psychiatry and Clinical Psychology, CHU de Nancy, Jeanne-d’Arc Hospital, 54200 Toul, France

    J-P Kahn

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  1. B Etain
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  3. F Mathieu
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Correspondence to S Jamain.

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SNAP25, GeneID:6616, HGNC:11132, Ensembl:ENSG00000132639

SNAP25a, NM_003081

SNAP25b, NM_130811

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Etain, B., Dumaine, A., Mathieu, F. et al. A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain. Mol Psychiatry 15, 748–755 (2010). https://doi.org/10.1038/mp.2008.148

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