| 1 | PLoS ONE 2009 -1 4: e6875 |
|---|---|
| PMID | 19721717 |
| Title | Apoptotic engulfment pathway and schizophrenia. |
| Abstract | Apoptosis has been speculated to be involved inschizophrenia. In a previously study, we reported the association of the MEGF10 gene with the disease. In this study, we followed the apoptotic engulfment pathway involving the MEGF10, GULP1,ABCA1and ABCA7 genes and tested their association with the disease. Ten, eleven and five SNPs were genotyped in the GULP1,ABCA1and ABCA7 genes respectively for the ISHDSF and ICCSS samples. In all 3 genes, we observed nominally significant associations. Rs2004888 at GULP1 was significant in both ISHDSF and ICCSS samples (p = 0.0083 and 0.0437 respectively). We sought replication in independent samples for this marker and found highly significant association (p = 0.0003) in 3 Caucasian replication samples. But it was not significant in the 2 Chinese replication samples. In addition, we found a significant 2-marker (rs2242436 * rs3858075) interaction between theABCA1和ISHDSF ABCA7基因样本(p = 0.0022)and a 3-marker interaction (rs246896 * rs4522565 * rs3858075) amongst the MEGF10, GULP1 andABCA1genes in the ICCSS sample (p = 0.0120). Rs3858075 in theABCA1gene was involved in both 2- and 3-marker interactions in the two samples. From these data, we concluded that the GULP1 gene and the apoptotic engulfment pathway are involved inschizophreniain subjects of European ancestry and multiple genes in the pathway may interactively increase the risks to the disease. |
| SCZ Keywords | schizophrenia |
| 2 | BMC Pharmacol. 2009 -1 9: 10 |
| PMID | 19715613 |
| Title | Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells. |
| Abstract | Disturbances in lipid homeostasis and myelination have been proposed in the pathophysiology ofschizophreniaand bipolar disorder. We have previously shown that several antipsychotic and antidepressant drugs increase lipid biosynthesis through activation of the Sterol Regulatory Element-Binding Protein (SREBP) transcription factors, which control the expression of numerous genes involved in fatty acid and cholesterol biosynthesis. The aim of the present proof-of-principle study was to investigate whether such drugs also affect lipid transport and export pathways in cultured human CNS and liver cells. Quantitative PCR and immunoblotting were used to determine the level of lipid transport genes in human glioblastoma (GaMg) exposed to clozapine, olanzapine, haloperidol or imipramine. The effect of some of these drugs was also investigated in human astrocytoma (CCF-STTG1), neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cells. We found significant transcriptional changes of cholesterol transport genes (ApoE,ABCA1, NPC1, NPC2, NPC1L1), which are predominantly controlled by the Liver X receptor (LXR) transcription factor. The up-regulation was observed after 24 to 48 hours of drug exposure, which is markedly delayed as compared to the drug-induced SREBP-controlled stimulation of lipid biosynthesis seen after 6 hours. Our data show that stimulation of cellular lipid biosynthesis by amphiphilic psychotropic drugs is followed by a transcriptional activation of cholesterol transport and efflux pathways. Such effects may be relevant for both therapeutic effects and metabolic adverse effects of psychotropic drugs. |
| SCZ Keywords | schizophrenia |
| 3 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1877-83 |
| PMID | 21839797 |
| Title | A polymorphism of the ABCA1 gene confers susceptibility to schizophrenia and related brain changes. |
| Abstract | The ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux through the transfer of cholesterol from the inner to the outer layer of the cell membrane and regulates extracellular cholesterol levels in the central nervous system. Several lines of evidence have indicated lipid and myelin abnormalities inschizophrenia. Initially, we examined the possible association of the polymorphisms of theABCA1gene (ABCA1) with susceptibility toschizophreniain 506 patients withschizophrenia(DSM-IV) and 941 controls. The observed association was then subject to a replication analysis in an independent sample of 511 patients and 539 controls. We further examined the possible effect of the risk allele on gray matter volume assessed with magnetic resonance imaging (MRI) in 86 patients withschizophrenia(49 males) and 139 healthy controls (47 males). 在最初的协会研究,1587 K等位基因e (rs2230808) was significantly more common in male patients withschizophreniathan in male controls. Although such a significant difference was not observed in the second sample alone, the increased frequency of the 1587 K allele in male patients remained to be significant in the combined male sample of 556 patients and 594 controls. Maleschizophreniapatients carrying the 1587 K allele had a smaller amount of gray matter volume than those who did not carry the allele. Our data suggest a male-specific association of the 1587 K allele ofABCA1with susceptibility toschizophreniaand smaller gray matter volume inschizophrenia. |
| SCZ Keywords | schizophrenia |