| 1 | Hum. Mol. Genet. 2008 Oct 17: 3212-22 |
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| PMID | 18658164 |
| Title | Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. |
| Abstract | schizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain unclear, it is now widely accepted that it is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene involved in neurodevelopment, including maturation of the cerebral cortex. To identify other susceptibility genes for schizophrenia, we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of 25 tagging single-nucleotide polymorphisms (SNPs) in a Japanese population. We identified a YWHAE SNP (rs28365859) that showed a highly significant difference between case and control samples, with higher minor allele frequencies in controls (P(allele) = 1.01 x 10(-5) and P(genotype) = 4.08 x 10(-5) in 1429 cases and 1728 controls). Both messenger RNA transcription and protein expression of 14-3-3epsilon were also increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor alleles compared with homozygous major allele subjects. To further investigate a potential role for YWHAE in schizophrenia, we studied YWHAE(+/-) mice in which the level of 14-3-3epsilon protein is reduced to 50% of that in wild-type littermates. These mice displayed weak defects in working memory in the eight-arm radial maze and moderately enhanced anxiety-like behavior in the elevated plus-maze. Our results suggest that YWHAE is a possible susceptibility gene that functions protectively in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | PLoS ONE 2011 -1 6: e23450 |
| PMID | 21853134 |
| Title | Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population. |
| Abstract | In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology. |
| SCZ Keywords | schizophrenia |
| 3 | Behav. Genet. 2011 Jul 41: 557-64 |
| PMID | 21184166 |
| Title | No association of the YWHAE gene with schizophrenia, major depressive disorder or bipolar disorder in the Han Chinese population. |
| Abstract | YWHAE is a gene encoding 14-3-3epsilon, which is highly conserved across species, from bacteria to humans, and binds to phosphoserine/phosphothreonine motifs in a sequence-specific manner. YWHAE has been reported to be associated with schizophrenia in a study based on the Japanese population. Here, we conducted a genetic association analysis between common SNPs in the YWHAE gene and psychiatric diseases including schizophrenia, major depressive disorder and bipolar disorder in Han Chinese samples (1140 schizophrenia cases, 1140 major depressive disorder cases, 1140 bipolar disorder cases and 1140 normal controls). We studied 11 SNPs, seven of which had previously been reported as significant, in YWHAE. No association was found with schizophrenia, major depressive disorder or bipolar disorder. Considering the size of our sample sets (power > 90%), our results suggest that the YWHAE does not play a major role in schizophrenia, major depressive disorder or bipolar disorder in the Han Chinese population. |
| SCZ Keywords | schizophrenia |
| 4 | J Clin Psychiatry 2012 Oct 73: e1276-82 |
| PMID | 23140658 |
| Title | Polymorphisms and haplotypes in the YWHAE gene increase susceptibility to bipolar disorder in Chinese Han population. |
| Abstract | schizophrenia and bipolar disorder are 2 major psychiatric illnesses sharing some specific genetic risk factors. Increasing evidence suggests the 2 illnesses might be more closely related than previously considered. To test this hypothesis, we investigated the allele and genotype frequencies of 11 single nucleotide polymorphisms (SNPs) and the haplotypes in these SNPs of the YWHAE gene. 1,982 patients were interviewed by 2 independent, experienced psychiatrists. Bipolar disorder diagnoses were made in strict accordance with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria using the Structured Clinical Interview for DSM-IV Axis I Disorders. In 2011, we conducted this genetic association analysis between 11 SNPs in YWHAE and bipolar disorder, involving a male group and a female group. In the analysis of allele and genotype frequencies, the SNP rs1873827 increased susceptibility to bipolar disorder in the male group. The haplotype analysis of CAC in rs3752826, rs2131431, and rs1873827 in the male group (?2 = 25.744, P = 3.97E-07, OR = 0.478 [95% CI, 0.358-0.639]) and of ACT and CAC in rs3752826, rs2131431, and rs1873827 in the female group (for ACT, ?2 = 30.365, P = 3.67E-08, OR = 0.040 [95% CI, 0.007-0.218]; for CAC, ?2 = 16.874, P = 4.04E-05, OR = 0.597 [95% CI, 0.466-0.765]) showed they are protective factors for bipolar disorder. However, the haplotype analysis of CAT in the male group (?2 = 19.874, P = 8.39E-06, OR = 2.314 [95% CI, 1.587-3.374]) and of AAC and CAT in the female group (for AAC, ?2 = 38.561, P = 5.47E-10, OR = 7.104 [95% CI, 3.471-14.540]; for CAT, ?2 = 25.497, P = 4.52E-07, OR = 2.076 [95% CI, 1.556-2.770]) showed they are risk factors for bipolar disorder. Considering the size of our sample, the results suggest that YWHAE does play a major role in bipolar disorder in the Han Chinese population. |
| SCZ Keywords | schizophrenia |
| 5 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jun 51: 166-71 |
| PMID | 24561237 |
| Title | The polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and orbitofrontal sulcogyral pattern in patients with schizophrenia and healthy subjects. |
| Abstract | An altered sulcogyral pattern in the orbitofrontal cortex (OFC) has been implicated in schizophrenia as a possible marker of abnormal neurodevelopment, while its genetic mechanism remains unknown. This magnetic resonance imaging study investigated the relationship between the polymorphism of YWHAE (rs28365859), a gene encoding 14-3-3epsilon that is a Disrupted-in-schizophrenia 1 (DISC1)-interacting molecule associated with neuronal development, and the OFC subtypes of the 'H-shaped' sulcus (Types I, II, and III) in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. The schizophrenia patients had significantly increased Type III (p = 0.004) and decreased Type I (p = 0.013) expression on the right hemisphere compared to the controls. The subjects carrying the protective C allele showed a decrease in Type III (p = 0.005) and an increase in Type I (p = 0.017) compared to the G allele homozygotes, especially for the healthy subjects in the left hemisphere. These results suggest a possible role for the YWHAE genotype in the early development of the OFC sulcogyral pattern, but its effect alone is not likely to explain the altered sulcogyral pattern in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 6 | PLoS ONE 2014 -1 9: e103571 |
| PMID | 25105667 |
| Title | The polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and brain morphology in schizophrenia: a voxel-based morphometric study. |
| Abstract | 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. In 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. 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 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. These 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. |
| SCZ Keywords | schizophrenia |
| 7 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jul -1: -1 |
| PMID | 26172220 |
| Title | Epistatic and gene wide effects in YWHA and aromatic amino hydroxylase genes across ADHD and other common neuropsychiatric disorders: Association with YWHAE. |
| Abstract | Monoamines critically modulate neurophysiological functions affected in several neuropsychiatric disorders. We therefore examined genes encoding key enzymes of catecholamine and serotonin biosynthesis (tyrosine and tryptophan hydroxylases-TH and TPH1/2) as well as their regulatory 14-3-3 proteins (encoded by YWHA-genes). Previous studies have focused mainly on the individual genes, but no analysis spanning this regulatory network has been reported. We explored interactions between these genes in Norwegian patients with adult attention deficit hyperactivity disorder (aADHD), followed by gene-complex association tests in four major neuropsychiatric conditions; childhood ADHD (cADHD), bipolar disorder, schizophrenia, and major depressive disorder. For interaction analyses, we evaluated 55 SNPs across these genes in a sample of 583 aADHD patients and 637 controls. For the gene-complex tests, we utilized the data from large-scale studies of The Psychiatric Genomics Consortium (PGC). The four major neuropsychiatric disorders were examined for association with each of the genes individually as well as in three complexes as follows: (1) TPH1 and YWHA-genes; (2) TH, TPH2 and YWHA-genes; and (3) all genes together. The results show suggestive epistasis between YWHAE and two other 14-3-3-genes - YWHAZ, YWHAQ - in aADHD (nominal P-value of 0.0005 and 0.0008, respectively). In PGC data, association between YWHAE and schizophrenia was noted (P?=?1.00E-05), whereas the combination of TPH1 and YWHA-genes revealed signs of association in cADHD, schizophrenia, and bipolar disorder. In conclusion, polymorphisms in the YWHA-genes and their targets may exert a cumulative effect in ADHD and related neuropsychiatric conditions, warranting the need for further investigation of these gene-complexes. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia |
| 8 | Schizophr Bull 2015 May 41: 744-53 |
| PMID | 25332407 |
| Title | Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility. |
| Abstract | Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency ?5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder. |
| SCZ Keywords | schizophrenia |