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.

Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation

“…This SNP appears to regulate the transcriptional activity of the TESC gene (Stein et al, 2012). This work was extended by Dannlowski et al who used different imaging methods and confirmed the association of the TESC gene SNPs with the reduction of volume in the gray matter of hippocampal formation, an area of relatively high tescalcin expression (Dannlowski et al, 2015). The authors also demonstrated an interaction of tescalcin with the rs2299403 variant of the RELN gene, encoding reelin, through an unknown molecular mechanism.…”

Obesity and major depression: Body-mass index (BMI) is associated with a severe course of disease and specific neurostructural alterations

“…The VBM8-toolbox (http://dbm.neuro.unijena.de/vbm) was used for preprocessing the structural images with default parameters as described in our previous work (Baune et al, 2012;Dannlowski et al, 2014Dannlowski et al, , 2012Opel et al, 2014;Redlich et al, 2014aRedlich et al, , 2014b. Briefly, images were bias-corrected, tissue classified, and normalized to MNI-space using linear (12-parameter affine) and non-linear transformations, within a unified model (Ashburner and Friston, 2005) including high-dimensional DARTEL-normalization.…”

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

“…In recent years, imaging genetics has emerged as a powerful tool for exploring the involvement of previously identified genetic variants in the etiology of psychiatric disorders. This approach characterizes the influence of genetic variants on brain structure and function that are the consequence of normal and abnormal biological pathways (Dannlowski et al, , 2014Erk et al, 2010;Stein et al, 2012).…”