| 1 | PLoS ONE 2010 -1 5: e9547 |
|---|---|
| PMID | 20221451 |
| Title | A recombination hotspot in a schizophrenia-associated region of GABRB2. |
| Abstract | schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the beta(2) subunit of GABA(A) receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes. In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (H(d)) over mutation rate (theta), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | J. Biol. Chem. 2010 Dec 285: 41337-47 |
| PMID | 21047779 |
| Title | Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. |
| Abstract | Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3? and Gsk-3?, are constitutively active, largely inhibitory kinases involved in signal transduction. Underscoring their biological significance, altered Gsk-3 activity has been implicated in diabetes, Alzheimer disease, schizophrenia, and bipolar disorder. Here, we demonstrate that deletion of both Gsk-3? and Gsk-3? in mouse embryonic stem cells results in reduced expression of the de novo DNA methyltransferase Dnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and Igf2r and hypomethylation of their corresponding imprinted control regions. Treatment of wild-type embryonic stem cells and neural stem cells with the Gsk-3 inhibitor, lithium, phenocopies the DNA hypomethylation at these imprinted loci. We show that inhibition of Gsk-3 by phosphatidylinositol 3-kinase (PI3K)-mediated activation of Akt also results in reduced DNA methylation at these imprinted loci. Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of Dnmt3a2 expression. In summary, we have identified a signal transduction pathway that is capable of altering the DNA methylation of imprinted loci. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | PLoS ONE 2010 -1 5: e9547 |
| PMID | 20221451 |
| Title | A recombination hotspot in a schizophrenia-associated region of GABRB2. |
| Abstract | schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the beta(2) subunit of GABA(A) receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes. In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (H(d)) over mutation rate (theta), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Epigenetics 2012 Feb 7: 155-63 |
| PMID | 22395465 |
| Title | Epigenetic and genetic variation at the IGF2/H19 imprinting control region on 11p15.5 is associated with cerebellum weight. |
| Abstract | IGF2 is a paternally expressed imprinted gene with an important role in development and brain function. Allele-specific expression of IGF2 is regulated by DNA methylation at three differentially methylated regions (DMRs) spanning the IGF2/H19 domain on human 11p15.5. We have comprehensively assessed DNA methylation and genotype across the three DMRs and the H19 promoter using tissue from a unique collection of well-characterized and neuropathologically-dissected post-mortem human cerebellum samples (n = 106) and frontal cortex samples (n = 51). We show that DNA methylation, particularly in the vicinity of a key CTCF-binding site (CTCF3) in the imprinting control region (ICR) upstream of H19, is strongly correlated with cerebellum weight. DNA methylation at CTCF3 uniquely explains ~25% of the variance in cerebellum weight. In addition, we report that genetic variation in this ICR is strongly associated with cerebellum weight in a parental-origin specific manner, with maternally-inherited alleles associated with a 16% increase in cerebellum weight compared with paternally-inherited alleles. Given the link between structural brain abnormalities and neuropsychiatric disease, an understanding of the epigenetic and parent-of-origin specific genetic factors associated with brain morphology provides important clues about the etiology of disorders such as schizophrenia and autism. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Neurotoxicology 2012 Oct 33: 1058-66 |
| PMID | 23227486 |
| Title | Effects of ketamine and its metabolites on ion currents in differentiated hippocampal H19-7 neuronal cells and in HEK293T cells transfected with ?-hslo subunit. |
| Abstract | Ketamine (KT), a dissociative anesthetic, is known to induce schizophrenia-like psychosis. The percentage of KT abuse has recently grown fast despite KT being a controlled drug. The mechanism of KT actions is related to the inhibition of NMDA receptors. Whether KT produces other effects on ion currents in hippocampal neurons remains unclear. In this study, we attempted to evaluate the possible effects of KT and other related compounds on ion currents in hippocampal neuron-derived H19-7 cells. This drug exerted an inhibitory effect on Ca(2+)-activated K(+) current (IK(Ca)) in these cells with an IC(50) value of 274 ?M. Pimaric acid (30 ?M) or abietic acid (30 ?M), known to stimulate large-conductance Ca(2+)-activated K(+) channels, reversed KT-induced inhibition of I(K)(Ca). In HEK293T cells expressing a-humans low poke, KT-induced inhibition of I(K)(Ca) still existed. Dehydronorketamine (300 ?M) had little or no effect on the IK(Ca) amplitude, while norketamine (300 ?M) slightly but significantly suppressed it. In inside?out configuration, KT applied to the intracellular face of the membrane did not alter single channel conductance of large-conductance Ca(2+)-activated K(+) (BKCa) channels; however, it did significantly reduce the probability of channel openings. Addition of KT was effective in depressing the peak amplitude of voltage-gated Na(+) current. Moreover, the presence of KT was noted to enhance the amplitude of membrane electroporation-induced inward currents (IMEP) in differentiated H19-7 cells. KT-stimulated IMEP was reversed by further application of LaCl(3) (100 ?M), but not by NMDA (30 ?M). The modulations by this compound of ion channels may contribute to the underlying mechanisms through which KT and its metabolites influence the electrical behavior of hippocampal neurons if similar findings occur in vivo. |
| SCZ Keywords | schizophrenia, schizophrenic |