Abstract
Background YWHAE 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.
Highlights
Schizophrenia is a heterogeneous psychiatric disorder with a multifactorial etiology in which multiple susceptibility genes interact with environmental factors [1,2]
As previous animal studies suggested the impact of YWHAE on the hippocampus [21], we examined the effect of its genotype on hippocampal volume using small volume correction (SVC) of voxel-based morphometry (VBM) analyses, with the hypothesis that subjects with the C allele would have a larger hippocampal volume, especially in schizophrenia patients
The subject overlap with our previous publication included 30/72 schizophrenia patients and 28/86 controls, where we reported the effect of Disrupted-inSchizophrenia 1 (DISC1) Ser704Cys polymorphism on brain morphology [18]
Summary
Schizophrenia is a heterogeneous psychiatric disorder with a multifactorial etiology in which multiple susceptibility genes interact with environmental factors [1,2]. Convergent evidence from neuroimaging studies in schizophrenia suggests subtle but widespread gray matter (GM) reductions predominantly in the frontal and temporo–limbic regions (e.g., hippocampus), at least partly as a consequence of early neurodevelopmental insult [3,4]. These brain morphologic changes in schizophrenia could be useful endophenotypes for unraveling the molecular etiopathology of this complex psychiatric disorder [5,6]. YWHAE is a possible susceptibility gene for schizophrenia that encodes 14-3-3epsilon, a Disrupted-inSchizophrenia 1 (DISC1)-interacting molecule, but the effect of variation in its genotype on brain morphology remains largely unknown
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