| 1 | Schizophr. Res. 2009 Apr 109: 121-9 |
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| PMID | 19232479 |
| Title | Does the presenilin 2 gene predispose to schizophrenia? |
| Abstract | Presenilins are a group of proteins playing an important role in the Notch, ErbB4 and Wnt signaling pathways possibly associated with schizophrenia. The gene coding for presenilin 2 (PSEN2) is located on 1q42 and adjacent to a balanced translocation t (1; 11) (q42; q14.3) that was found to co-segregate within family members of patients with schizophrenia. We thus hypothesized that PSEN2 may contribute to the pathogenesis of schizophrenia. Five functional SNPs (rs1295645, rs11405, rs6759, rs1046240 and rs8383) present in the coding regions of the PSEN2 gene were tested in 410 patients with schizophrenia and 355 controls in a Chinese Han population. Association analysis showed a weak association for rs1295645 and the rs1295645-T allele was involved in increased risk of schizophrenia (corrected p=0.045, OR=1.32, 95% CI 1.04-1.68). The T-C-T-T-T haplotype also showed association with increased risk of the illness (p=1.8x10(-5), OR=3.37, 95% CI 1.33-8.51). Analysis of gene expression demonstrated that PSEN2 mRNA levels in peripheral leukocytes were significantly lower in the patient group than in the control group and that expression levels of the PSEN2 gene were significantly correlated to its genotypes. Analysis of clinical profiles showed an association between the PSEN2 gene and some clinical phenotypes scored using the PANSS. The present results suggest that the PSEN2 gene may be a novel candidate involved in the development of certain psychotic symptoms of schizophrenia although the initial finding needs further replication in a large sample size. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Mar 162B: 191-200 |
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| PMID | 23335491 |
| Title | A combined study of genetic association and brain imaging on the DAOA gene in schizophrenia. |
| Abstract | While there has been no objective biomarker available for both diagnosis and prognosis of schizophrenia, compelling evidence suggests that the glutamatergic system may influence susceptibility to schizophrenia. To test genetic association of the glutamatergic system with schizophrenia and abnormal brain activities in resting-state patients with schizophrenia, a two-stage association study was performed in 454 patients and 480 controls, followed by regional homogeneity (ReHo) analysis of resting-state functional magnetic resonance imaging in 48 first-episode medication-free patients and 43 well-matched controls. The differences in ReHo between genotypes of interest were initially tested by the Student's t-test and the 2 × 2 (genotypes × disease status) ANOVA was then performed to identify the main effects of genotypes, disease status and their interactions in schizophrenia. The stage-1 study showed association of the DAOA and PSEN2 genes with schizophrenia in a small sample; the stage-2 study with an expanded sample confirmed the disease association for 2-SNP and 3-SNP haplotypes, and the cis-phase interactions between rs2391191 and some other SNPs in the DAOA gene. Four clusters with altered ReHo in the bilateral culmen, left putamen and left cuneus were associated with rs2391191. Main effects of rs2391191 genotypes were found in the left putamen. The left cuneus showed a genotype × disease status interaction. In conclusion, the DAOA gene may confer genetic risk of schizophrenia and associate with the altered ReHo in schizophrenia; genotype effect and its interaction with disease status may contribute to the altered ReHo, leading to specific ReHo in schizophrenic brain due to glutamatergic modulation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Mar 162B: 191-200 |
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| PMID | 23335491 |
| Title | A combined study of genetic association and brain imaging on the DAOA gene in schizophrenia. |
| Abstract | While there has been no objective biomarker available for both diagnosis and prognosis of schizophrenia, compelling evidence suggests that the glutamatergic system may influence susceptibility to schizophrenia. To test genetic association of the glutamatergic system with schizophrenia and abnormal brain activities in resting-state patients with schizophrenia, a two-stage association study was performed in 454 patients and 480 controls, followed by regional homogeneity (ReHo) analysis of resting-state functional magnetic resonance imaging in 48 first-episode medication-free patients and 43 well-matched controls. The differences in ReHo between genotypes of interest were initially tested by the Student's t-test and the 2 × 2 (genotypes × disease status) ANOVA was then performed to identify the main effects of genotypes, disease status and their interactions in schizophrenia. The stage-1 study showed association of the DAOA and PSEN2 genes with schizophrenia in a small sample; the stage-2 study with an expanded sample confirmed the disease association for 2-SNP and 3-SNP haplotypes, and the cis-phase interactions between rs2391191 and some other SNPs in the DAOA gene. Four clusters with altered ReHo in the bilateral culmen, left putamen and left cuneus were associated with rs2391191. Main effects of rs2391191 genotypes were found in the left putamen. The left cuneus showed a genotype × disease status interaction. In conclusion, the DAOA gene may confer genetic risk of schizophrenia and associate with the altered ReHo in schizophrenia; genotype effect and its interaction with disease status may contribute to the altered ReHo, leading to specific ReHo in schizophrenic brain due to glutamatergic modulation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Neuropsychiatr Dis Treat 2015 -1 11: 2315-22 |
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| PMID | 26396515 |
| Title | Identification of two novel mutations, PSEN1 E280K and PRNP G127S, in a Malaysian family. |
| Abstract | Alzheimer's disease (AD) is the most common form of dementia, which can be categorized into two main forms: early onset AD and late onset AD. The genetic background of early onset AD is well understood, and three genes, the APP, PSEN1, and PSEN2 have been identified as causative genes. In the current study, we tested three siblings from Malaysia who were diagnosed with early onset dementia, as well as their available family members. The family history was positive as their deceased father was similarly affected. Patients were tested for mutations in APP, PSEN1, PSEN2, and PRNP. A novel variant, E280K, was discovered in exon 8 of PSEN1 in the three siblings. In silico analyses with SIFT, SNAP, and PolyPhen2 prediction tools and three-dimensional modeling were performed, and the results suggested that the mutation is probably a pathogenic variant. Two additional pathogenic mutations were previously been described for codon 280, E280A, and E280G, which could support the importance of the E280 residue in the PS1 protein contributing to the pathogenic nature of E280K. Additional ten family members were screened for the E280K mutation, and all of them were negative. Six of them presented with a variety of neuropsychiatric symptoms, including learning disabilities, epilepsy, and schizophrenia, while four family members were asymptomatic. A novel PRNP G127S mutation was found in a step-niece of the three siblings harboring the PSEN1 E280K mutation. In silico predictions for PRNP G127S mutation suggested that this might be possibly a damaging variant. Additional studies to characterize PRNP G127S would be necessary to further understand the effects of this mutation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | J. Alzheimers Dis. 2016 Mar 52: 581-608 |
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| PMID | 27031468 |
| Title | The Zebrafish Equivalent of Alzheimer's Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress. |
| Abstract | Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer's disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2, PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase ?-secretase activity and suppress the unfolded protein response (UPR), but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology. |
| SCZ Keywords | schizophrenia, schizophrenic |