Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure.
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.
1] Department of Psychiatry, University of Münster, Münster, Germany [2] Department of Psychiatry, University of Marburg, Marburg, Germany.
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Dannlowski
1] Department of Psychiatry, University Medicine Greifswald, HELIOS-Hospital Stralsund, Stralsund, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
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Grabe
German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
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Wittfeld
Department of Psychiatry, University of Münster, Münster, Germany.
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Klaus
Department of Psychiatry, University of Marburg, Marburg, Germany.
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Konrad
Department of Psychiatry, University of Münster, Münster, Germany.
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Grotegerd
Department of Psychiatry, University of Münster, Münster, Germany.
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Redlich
1] Department of Psychiatry, University of Münster, Münster, Germany [2] Department of Psychosomatic Medicine and Psychotherapy, University of Leipzig, Leipzig, Germany.
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Suslow
Department of Psychiatry, University of Münster, Münster, Germany.
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Opel
Department of Psychiatry, University of Münster, Münster, Germany.
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Ohrmann
Department of Psychiatry, University of Münster, Münster, Germany.
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Bauer
Department of Psychiatry, University of Münster, Münster, Germany.
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Zwanzger
Department of Psychiatry, University of Münster, Münster, Germany.
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Laeger
Department of Psychiatry, University of Münster, Münster, Germany.
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Hohoff
Department of Psychiatry, University of Münster, Münster, Germany.
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Arolt
Department of Clinical Radiology, University of Münster, Münster, Germany.
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Heindel
Department of Neurology, University of Münster, Münster, Germany.
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Deppe
Department of Psychiatry, University of Würzburg, Würzburg, Germany.
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Domschke
Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
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Hegenscheid
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
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Völzke
Discipline of Psychiatry, School of Medicine, University of Adelaide: North Terrace, Adelaide, SA, Australia.
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Stacey
Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
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Meyer Zu Schwabedissen
Department of Clinical Radiology, University of Münster, Münster, Germany.
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Kugel
Discipline of Psychiatry, School of Medicine, University of Adelaide: North Terrace, Adelaide, SA, Australia.
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Baune
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D005838:Genotype; D066128:Gray Matter / Q000098:blood supply / Q000378:metabolism; D006624:Hippocampus / Q000033:anatomy & histology* / Q000098:blood supply; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C486009:TESC protein, human; C000717127:RELN protein, human; D012697:Serine Endopeptidases; D010100:Oxygen