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Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism

Molecular Psychiatry volume 11, pages 1003–1015 (2006)Cite this article

Abstract

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

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Acknowledgements

This project was supported by grants from the Friedrich-Baur-Foundation (FBI 0046/2002 and 0051/2000), the Foerderprogramm fuer Forschung und Lehre of the Ludwig-Maximilian-University of Munich (Reg. no. 372) and the Deutsche Forschungsgemeinschaft (DFG BA 2309/1-1) (LMU), as well as the Bavarian Ministry of Commerce and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN) (Reg. 01GS0481) (MPI). We would like to thank S de Jonge and K Neuner for expert technical assistance, J Klesing for support in the preparation of the manuscript and Dr Ruppert and his team at the GRC for genotyping. We are responsible for the contents of this publication.

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  1. T C Baghai and E B Binder: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University of Munich, Munich, Germany

    T C Baghai, C Schule, D Eser, P Zwanzger, P Zill, T Deiml, C Nothdurfter, H-J Möller, R Rupprecht & B Bondy

  2. Max-Planck Institute of Psychiatry, Munich, Germany

    E B Binder, D Salyakina, S Lucae, C Haberger, M Ising, M Uhr, S Modell, F Holsboer & B Müller-Myhsok

  3. GSF National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany

    T Illig & H-E Wichmann

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Baghai, T., Binder, E., Schule, C. et al. Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Mol Psychiatry 11, 1003–1015 (2006). https://doi.org/10.1038/sj.mp.4001884

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