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

<div><p>Background</p><p><i>YWHAE</i> is a possible susceptibility gene for schizophrenia that encodes 14-3-3epsilon, a Disrupted-in-Schizophrenia 1 (<i>DISC1</i>)-interacting molecule, but the effect of variation in its genotype on brain morphology remains largely unknown.</p><p>Methods</p><p>In this voxel-based morphometric magnetic resonance imaging study, we conducted whole-brain analyses regarding the effects of <i>YWHAE</i> single-nucleotide polymorphisms (SNPs) (<i>rs28365859, rs11655548, and rs9393</i>) and <i>DISC1</i> SNP (<i>rs821616</i>) 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 <i>rs28365859</i> genotype specifically on hippocampal volume.</p><p>Results</p><p>Whole-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 <i>rs28365859</i> in the left insula and right putamen. The protective C allele carriers of <i>rs28365859</i> 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 <i>rs28365859</i> and <i>DISC1</i> SNP on gray matter volume.</p><p>Conclusions</p><p>These different effects of the <i>YWHAE</i> (<i>rs28365859</i>) 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 <i>YWHAE</i> SNPs in the pathophysiology of schizophrenia.</p></div

The <i>YWHAE</i> (<i>rs28365859</i>) genotype-by-diagnosis interaction on gray matter volume.

<p>The regions showing interaction in all subjects are displayed by a hot colormap. The color bar shows t values corresponding to the color in the figure.</p

Impact of the <i>rs28365859</i> genotype on gray matter volume of the right hippocampus in schizophrenia.

<p>Age, sex, illness duration, and medication dose were used as covariates. The protective C allele carriers had a significantly larger right hippocampus than the G allele homozygotes. Anatomical localizations are displayed on the normal template MR images in three directions. The color bar shows t values corresponding to the color in the figure.</p

Effect of <i>rs28365859</i> genotype on right hippocampal gray matter volume.

<p>C+, subjects with C allele; C−, subjects without C allele; doi, duration of illness; FWE, family-wise error; med, daily medication dose; SzC+, schizophrenia patients with C allele; SzC−, schizophrenia patients without C allele.</p>a<p>There were no suprathreshold clusters for other contrasts.</p

Impact of the <i>rs28365859</i> genotype on gray matter volume of the right putamen in healthy controls.

<p>The G allele homozygotes had a significantly larger right putamen than the C allele carriers. Anatomical localizations are displayed on the normal template MR images in three directions. The color bar shows t values corresponding to the color in the figure.</p

Clinical and <i>YWHAE</i> genotypic description of schizophrenia patients and healthy controls.

<p>Values represent means ± SDs. Con, controls; SANS, Scale for the Assessment of Negative Sympoms; SAPS, Scale for the Assessment of Positive Symptoms; Sz, schizophrenia.</p>a)<p>Data missing for one patient.</p

Impact of the <i>rs28365859</i> genotype on gray matter volume of left insula in schizophrenia.

<p>Age, sex, illness duration, and medication dose were used as covariates. The protective C allele carriers had a significantly larger left insula than the G homozygotes. Anatomical localizations are displayed on the normal template MR images in three directions. The color bar shows t values corresponding to the color in the figure.</p

Data_Sheet_1_Validation and Factor Analysis of the Japanese Version of the Highs Scale in Perinatal Women.docx

<p>Background: The Highs scale has been developed to evaluate hypomanic symptoms in the first postpartum week. However, it has not been elucidated whether this scale is also applicable to pregnant women. To address this issue, we confirmed the factor structure, reliability, and validity of the Japanese version of the Highs scale for pregnant and postpartum women.</p><p>Methods: 418 women provided effective responses to both the Highs scale and the Edinburgh Postnatal Depression Scale (EPDS) during early pregnancy (before week 25), late pregnancy (around week 36), at 5 days and at 1 month after delivery. Subjects were randomly divided into two groups, and exploratory and confirmatory factor analyses were performed for each group. Cronbach's alpha was calculated and the correlation of the Highs scale with EPDS was analyzed. The correlation between the subscales was analyzed at four time points, and the correlation of subscales between the four time points was confirmed.</p><p>Results: This scale was found to have the two-factor structure with elation and agitation subscales. The two subscales had reasonable internal consistency at all time points (Cronbach's alpha range: Factor 1, 0.696–0.758; Factor 2, 0.553–0.694). The overall scale had reasonable internal consistency at all time points (Cronbach's alpha range: 0.672–0.738). Based on the correlation analysis of the two subscales and EPDS, discriminative and convergent validity were indicated at all time points, confirming the construct validity of the Highs scale. Subscale scores showed a significant correlation with EPDS at all time points (r = 0.388, 0.384, 0.498, and 0.442, p < 0.01).</p><p>Conclusions: The Japanese version of the Highs scale is reliable and valid, and can be applied for evaluating the hypomanic symptoms during pregnancy and postpartum period.</p

Effect of <i>rs28365859</i> genotype and genotype-by-diagnosis interaction on gray matter volume.

<p>ConC+, controls with C allele; ConC−, controls without C allele; doi, duration of illness; FWE, family-wise error; Lt, left; med, daily medication dose; Rt, right; SVC, small volume correction; SzC+, schizophrenia patients with C allele; SzC−, schizophrenia without C allele.</p>a<p>There were no suprathreshold clusters for other contrasts.</p

Resequencing and Association Analysis of <i>PTPRA</i>, a Possible Susceptibility Gene for Schizophrenia and Autism Spectrum Disorders

<div><p>Background</p><p>The <i>PTPRA</i> gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.</p><p>Methods</p><p>We sequenced the protein-encoding areas of the <i>PTPRA</i> gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3′UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls.</p><p>Results</p><p>Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3′UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.</p><p>Major Conclusions</p><p>No evidence was seen for the association of rare, missense mutations in the <i>PTPRA</i> gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.</p></div