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Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure

Abstract

In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

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Acknowledgements

The study was supported by grants of Innovative Medizinische Forschung (IMF) of the Medical Faculty of Münster (DA120903, DA111107 and DA211012 to UD), Rolf-Dierichs-Stiftung (ZUW80037 to UD), and Interdisziplinäres Zentrum für Klinische Forschung (IZKF) of the Medical Faculty of Münster. The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (grants 01ZZ9603, 01ZZ0103 and 01ZZ0403). Genome-wide data and MRI scans were supported by the Federal Ministry of Education and Research (grant 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The work is also supported by the ‘Greifswald Approach to Individualized Medicine’ (GANI_MED) network funded by the Federal Ministry of Education and Research (grant 03IS2061A). Molecular analyses were supported by the National Health and Medical Research Council (NHMRC; grant APP 1003788 to BTB).

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Professor Volker Arolt, MD, PhD is a member of advisory boards and/or gave presentations for the following companies: AstraZeneca, Janssen-Organon, Lilly, Lundbeck, Servier, Pfizer and Wyeth. He also receives funds from the German Ministry of Education and Research (BMBF) and from the European Union (EU-FP7). Professor Bernhard T Baune, MD, PhD, MPH is a member of advisory boards, received funding and/or gave presentations for the following companies: AstraZeneca, Lundbeck, Pfizer, Servier and Wyeth. He receives funding from the National Health and Medical Research Council (NHMRC) Australia. Professsor Katharina Domschke, MA, MD, PhD, received speaker’s honoraria by Pfizer, Lilly and Bristol–Myers Squibb, has been a consultant for Johnson&Johnson, and has received funding by AstraZeneca. Professor Hans J Grabe received speakers honoraria by Lilly and Servier. Professsor Peter Zwanzger has received speaker fees from Pfizer, Servier, Lilly, AstraZeneca and Bristol–Myers Squibb, is on the advisory board of Pfizer, is a consultant for Ironwood Pharmaceuticals, and has received funding from AstraZeneca. All other authors declare no conflict of interest.

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Dannlowski, U., Grabe, H., Wittfeld, K. et al. Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure. Mol Psychiatry 20, 398–404 (2015). https://doi.org/10.1038/mp.2014.39

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