1] Department of Psychiatry, University of Münster, Münster, Germany [2] Department of Psychiatry, University of Marburg, Marburg, Germany.
1] Department of Psychiatry, University Medicine Greifswald, HELIOS-Hospital Stralsund, Stralsund, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
Mol Psychiatry. 2015 Mar;20(3):398-404. doi: 10.1038/mp.2014.39. Epub 2014 Apr 29.
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.
在两项大型全基因组关联研究中，一个参与 TESC 基因调控的基因间单核苷酸多态性（SNP；rs7294919）与海马体体积有关。使用多模态脑全结构和功能成像进一步表征 TESC 基因的神经生物学效应是必要的。基于体素的形态计量学（VBM8）用于分析两个大型、特征明确的欧洲西部血统健康个体样本（明斯特样本，N=503；SHIP-TREND，N=721）中 rs7294919 与局部灰质体积之间的关联。在亚样本中，使用弥散张量成像（DTI）研究白质纤维结构，通过功能磁共振成像（fMRI）在面部情绪处理期间测量边缘响应（分别为 N=220 和 N=264）。此外，还探索了基因与环境（G×E）相互作用以及与先前发现与海马体大小相关的基因（FKBP5、Reelin、IL-6、TNF-α、BDNF 和 5-HTTLPR/rs25531）的 SNP 的基因与基因相互作用。我们证明了 rs7294919 在两个样本中对海马灰质体积有高度显著的影响。在全脑分析中，除了海马结构和相邻的颞叶结构外，没有其他脑区与 rs7294919 相关。在两个样本中，都没有基因型对 DTI 和 fMRI 结果（包括功能连接测量）的影响。在两个样本中都没有发现与儿童期虐待的 G×E 相互作用。然而，在 Reelin 基因中发现了 rs7294919 与 rs2299403 之间的相互作用，该相互作用在经过多次比较校正后仍然存在。我们得出结论，rs7294919 对海马灰质结构有高度稳健和区域特异性的影响，但对其他神经精神病学相关的成像标记物没有影响。TESC 和 RELN 之间的生物学相互作用表明观察到的发现具有神经发育起源，这需要进一步的机制研究。
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