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Effects of the G(−656)A variant on CREB1 promoter activity in a neuronal cell line: Interactions with gonadal steroids and stress

Molecular Psychiatry volume 14, pages 390–397 (2009)Cite this article

Abstract

Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33–35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position −656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A−656 allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene–environment interactions that contribute to the emergence of MDD in clinical populations.

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Acknowledgements

This work was supported by research project Grants MH43261, MH60866 and MH47346 from the National Institute of Mental Health (GSZ).

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Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    G S Zubenko & H B Hughes III

  2. Department of Biological Sciences, Mellon College of Science, Carnegie-Mellon University, Pittsburgh, PA, USA

    G S Zubenko

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  1. G S Zubenko
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Correspondence to G S Zubenko.

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Zubenko, G., Hughes, H. Effects of the G(−656)A variant on CREB1 promoter activity in a neuronal cell line: Interactions with gonadal steroids and stress. Mol Psychiatry 14, 390–397 (2009). https://doi.org/10.1038/mp.2008.23

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