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  Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression

Hennings, J. M., Kohli, M. A., Uhr, M., Holsboer, F., Ising, M., & Lucae, S. (2019). Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 95: UNSP 109686. doi:10.1016/j.pnpbp.2019.109686.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-F6E9-F Version Permalink: http://hdl.handle.net/21.11116/0000-0005-F6EA-E
Genre: Journal Article

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Hennings, Johannes M.1, 2, 3, Author              
Kohli, Martin A.4, Author              
Uhr, Manfred3, 4, 5, 6, 7, Author              
Holsboer, Florian2, 4, 6, 8, Author              
Ising, Marcus2, 4, 6, 9, Author              
Lucae, Susanne1, 2, Author              
Affiliations:
1RG Susanne Lucae, Psychiatric Pharmacogenetics, Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040299              
2Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              
3Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
4Max Planck Institute of Psychiatry, Max Planck Society, ou_1607137              
5Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035294              
6Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              
7AG Uhr, Manfred, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society, ou_1607163              
8Emeritiertes wissenschaftliches Mitglied, Max Planck Institute of Psychiatry, Max Planck Society, ou_2074301              
9RG Marcus Ising, Molecular Psychology, Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040298              

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 Abstract: Major depression is a stress-related disorder with robust clinical and preclinical data implicating that both, dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis and of the neurotrophin system of the brain are involved in the pathophysiology. Genetic variations within the brain-derived neurotrophic factor (BDNF) gene region, a major representative of the brain neurotrophins, are suggested to influence response to antidepressant treatment. Specifically, we recently identified two BDNF single nucleotide polymorphisms (SNP), rs2049046 and rs11030094, as associated with antidepressant treatment response in a large pharmacogenetic study of hospitalized patients. We now analyzed these two SNPs in a sub-sample for their association with HPA axis dysregulation using the combined dexamethasone suppression/corticotropin releasing hormone challenge (dex/CRH) test at hospital admission (N = 266) and at discharge (N = 190). Rs11030094, located 3' outside the coding region of BDNF, is also located in an intron of BDNFOS coding for a functional antagonist of BDNF. We further included the non-synonymous Val66Met (rs6265) polymorphism in our analysis, for which - albeit being extensively studied - conflicting results in respect to its role in antidepressant treatment response have been reported. Similar to the previous analysis, rs2049046 and rs11030094 showed a significant effect on antidepressant response. In a gene-dose dependent manner, we found significant lower cortisol responses to the dex/CRH test at discharge in carriers of the respective SNP alleles ('T' of rs2049046 and 'G' of rs11030094) that were associated with antidepressant response (beneficial alleles). These genetic effects on HPA axis regulation were independent of age, sex, medication and depressive symptomatology. Although not reaching statistical significance, the same direction of effect was observed for cortisol at admission, as well as the ACTH response at admission and discharge. An interaction analysis of both SNPs revealed highest cortisol levels in subjects that were non-carriers of both beneficial alleles. The Val66Met (rs6265) was neither associated with antidepressant response nor with HPA axis regulation. Our findings provide further evidence for an interaction of the HPA axis and the neurotrophin system in major depression. This study stresses the importance investigating BDNF variants beyond the extensively studied Val66Met polymorphism. In-depth analyses of both pathophysiologically relevant systems may point to possible new targets for pharmaceutical intervention and precision medicine of major depression in the future.

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 Dates: 2019-12-20
 Publication Status: Published online
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Title: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
Source Genre: Journal
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Pages: - Volume / Issue: 95 Sequence Number: UNSP 109686 Start / End Page: - Identifier: ISSN: 0278-5846