The Polymorphism of YWHAE, a Gene Encoding 14-3-3Epsilon, and Brain Morphology in Schizophrenia: A Voxel-Based Morphometric Study

BackgroundYWHAE is a possible susceptibility gene for schizophrenia that encodes 14-3-3epsilon, a Disrupted-in-Schizophrenia 1 (DISC1)-interacting molecule, but the effect of variation in its genotype on brain morphology remains largely unknown.MethodsIn this voxel-based morphometric magnetic resonance imaging study, we conducted whole-brain analyses regarding the effects of YWHAE single-nucleotide polymorphisms (SNPs) (rs28365859, rs11655548, and rs9393) and DISC1 SNP (rs821616) on gray matter volume in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. On the basis of a previous animal study, we also examined the effect of rs28365859 genotype specifically on hippocampal volume.ResultsWhole-brain analyses showed no significant genotype effect of these SNPs on gray matter volume in all subjects, but we found significant genotype-by-diagnosis interaction for rs28365859 in the left insula and right putamen. The protective C allele carriers of rs28365859 had a significantly larger left insula than the G homozygotes only for schizophrenia patients, while the controls with G allele homozygosity had a significantly larger right putamen than the C allele carriers. The C allele carriers had a larger right hippocampus than the G allele homozygotes in schizophrenia patients, but not in healthy controls. No significant interaction was found between rs28365859 and DISC1 SNP on gray matter volume.ConclusionsThese different effects of the YWHAE (rs28365859) genotype on brain morphology in schizophrenia and healthy controls suggest that variation in its genotype might be, at least partly, related to the abnormal neurodevelopment, including in the limbic regions, reported in schizophrenia. Our results also suggest its specific role among YWHAE SNPs in the pathophysiology of schizophrenia.背景 YWHAE是精神分裂症的潜在易感基因，其编码14-3-3ε（14-3-3epsilon）——一种与精神分裂症断裂基因1（Disrupted-in-Schizophrenia 1, DISC1）相互作用的分子，但该基因基因型变异对脑形态学的影响目前仍未明确。 方法 本研究采用体素形态学磁共振成像（voxel-based morphometric magnetic resonance imaging）技术，针对由72名精神分裂症患者与86名健康对照组成的日本人群队列开展全脑分析，探究YWHAE单核苷酸多态性（single-nucleotide polymorphisms, SNPs）（rs28365859、rs11655548及rs9393）与DISC1单核苷酸多态性rs821616对脑灰质体积的影响。基于既往动物研究，我们还专门针对rs28365859基因型对海马体积的影响进行了分析。 结果 全脑分析显示，在全部受试者中，上述单核苷酸多态性的基因型对脑灰质体积无显著主效应，但我们观察到rs28365859的基因型×诊断交互作用在左侧岛叶与右侧壳核中具有统计学意义。仅在精神分裂症患者亚组中，rs28365859的保护性C等位基因携带者的左侧岛叶体积显著大于G等位基因纯合子；而在健康对照亚组中，G等位基因纯合子的右侧壳核体积则显著大于C等位基因携带者。在精神分裂症患者中，C等位基因携带者的右侧海马体积显著大于G等位基因纯合子，但该差异未在健康对照中出现。未观察到rs28365859与DISC1单核苷酸多态性对脑灰质体积存在显著交互作用。 结论 YWHAE基因rs28365859基因型对精神分裂症患者与健康对照的脑形态学影响存在差异，提示该基因的基因型变异可能至少部分参与了精神分裂症报道的异常神经发育过程（包括边缘系统区域）。本研究结果同时提示，在YWHAE的单核苷酸多态性位点中，rs28365859在精神分裂症病理生理机制中发挥特定作用。