| 1 | Neuropsychobiology 2000 -1 42: 172-4 |
|---|---|
| PMID | 11096331 |
| Title | Association study of apolipoprotein E epsilon4 with clinical phenotype and clozapine response in schizophrenia. |
| Abstract | schizophrenic patients with the apolipoprotein E (APOE = gene; APOE = protein) epsilon4 allele exhibited lower psychosis scores than patients without the epsilon4 allele in previous reports. The present study tested the hypothesis that the APOE epsilon4 allele confers association with the clinical manifestations of schizophrenia or clozapine response. A total of 95 schizophrenic patients who were treatment resistant were included in the study. The results demonstrated that the presence of the APOE epsilon4 allele did not influence the response to clozapine in schizophrenic patients, neither was the baseline psychopathology related to the APOE epsilon4 allele. Given the multiple functions of the APOE protein in the brain, further study of the influence of APOE on CNS medication response is needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Neuropsychobiology 2000 -1 42: 172-4 |
| PMID | 11096331 |
| Title | Association study of apolipoprotein E epsilon4 with clinical phenotype and clozapine response in schizophrenia. |
| Abstract | schizophrenic patients with the apolipoprotein E (APOE = gene; APOE = protein) epsilon4 allele exhibited lower psychosis scores than patients without the epsilon4 allele in previous reports. The present study tested the hypothesis that the APOE epsilon4 allele confers association with the clinical manifestations of schizophrenia or clozapine response. A total of 95 schizophrenic patients who were treatment resistant were included in the study. The results demonstrated that the presence of the APOE epsilon4 allele did not influence the response to clozapine in schizophrenic patients, neither was the baseline psychopathology related to the APOE epsilon4 allele. Given the multiple functions of the APOE protein in the brain, further study of the influence of APOE on CNS medication response is needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Neuropsychobiology 2000 -1 42: 66-8 |
| PMID | 10940761 |
| Title | Apolipoprotein E epsilon3 allele is not a risk factor of schizophrenia: a study of 314 Japanese patients. |
| Abstract | The association between apolipoprotein E (APOE) alleles and schizophrenia has remained controversial. A recent report claiming that APOE epsilon3 Taiwan Chinese carriers have an increased risk of schizophrenia prompted us to investigate the allele frequency in a large group of Japanese schizophrenic patients. Serum samples were obtained from 314 schizophrenic patients and 188 controls in Japan and examined using isoelectric focusing/immunoblotting. There were no significant differences in APOE allele frequencies between schizophrenic patients and controls and in the odds ratios for schizophrenia among the epsilon2, epsilon3 and epsilon4 carriers. In contrast to the report from Taiwan, our findings and results of the majority of previous studies suggest no effects of APOE alleles on the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Psychiatr. Genet. 2000 Jun 10: 73-7 |
| PMID | 10994644 |
| Title | Apolipoprotein E genotype in Spanish schizophrenic patients. |
| Abstract | Apolipoprotein E (APOE) is a lipoprotein that, in the central nervous system, is thought to play a role in neuronal growth and repair. APOE has three isoforms (APOE2, APOE3 and APOE4) coded by three different alleles (epsilon2, epsilon3 and epsilon4). Evidence from family, twin and adoption studies suggest that there is an important genetic contribution to the etiology of schizophrenia. schizophrenia is in some cases associated with cognitive impairment similar to that of Alzheimer patients; therefore, one may postulate that the APOE gene, whose role in the dementia of Alzheimer's type has been clearly demonstrated, may also be involved in schizophrenia. In the present study, we have genotyped 114 schizophrenic Spanish patients and 94 healthy matched controls, and found no association between the APOE genotype and schizophrenia. Subdivision of patients in clinical subgroups showed a slight increase of APOE4 in early-age onset of the disease and a slight decrease in positive family history for psychiatric diseases; the group with a poor response to neuroleptic drugs had a lower APOE2 allele frequency. However, as the differences did not reach statistical significance, we cannot draw evidence of an association. Our negative data do not support an involvement of APOE in schizophrenia, and suggest that the underlying mechanism for the cognitive impairment found in schizophrenic patients is not related to that of Alzheimer's patients nor to a higher prevalence of the APOE allele 4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Neuropsychobiology 2000 -1 42: 66-8 |
| PMID | 10940761 |
| Title | Apolipoprotein E epsilon3 allele is not a risk factor of schizophrenia: a study of 314 Japanese patients. |
| Abstract | The association between apolipoprotein E (APOE) alleles and schizophrenia has remained controversial. A recent report claiming that APOE epsilon3 Taiwan Chinese carriers have an increased risk of schizophrenia prompted us to investigate the allele frequency in a large group of Japanese schizophrenic patients. Serum samples were obtained from 314 schizophrenic patients and 188 controls in Japan and examined using isoelectric focusing/immunoblotting. There were no significant differences in APOE allele frequencies between schizophrenic patients and controls and in the odds ratios for schizophrenia among the epsilon2, epsilon3 and epsilon4 carriers. In contrast to the report from Taiwan, our findings and results of the majority of previous studies suggest no effects of APOE alleles on the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Psychiatr. Genet. 2000 Jun 10: 73-7 |
| PMID | 10994644 |
| Title | Apolipoprotein E genotype in Spanish schizophrenic patients. |
| Abstract | Apolipoprotein E (APOE) is a lipoprotein that, in the central nervous system, is thought to play a role in neuronal growth and repair. APOE has three isoforms (APOE2, APOE3 and APOE4) coded by three different alleles (epsilon2, epsilon3 and epsilon4). Evidence from family, twin and adoption studies suggest that there is an important genetic contribution to the etiology of schizophrenia. schizophrenia is in some cases associated with cognitive impairment similar to that of Alzheimer patients; therefore, one may postulate that the APOE gene, whose role in the dementia of Alzheimer's type has been clearly demonstrated, may also be involved in schizophrenia. In the present study, we have genotyped 114 schizophrenic Spanish patients and 94 healthy matched controls, and found no association between the APOE genotype and schizophrenia. Subdivision of patients in clinical subgroups showed a slight increase of APOE4 in early-age onset of the disease and a slight decrease in positive family history for psychiatric diseases; the group with a poor response to neuroleptic drugs had a lower APOE2 allele frequency. However, as the differences did not reach statistical significance, we cannot draw evidence of an association. Our negative data do not support an involvement of APOE in schizophrenia, and suggest that the underlying mechanism for the cognitive impairment found in schizophrenic patients is not related to that of Alzheimer's patients nor to a higher prevalence of the APOE allele 4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | J. Korean Med. Sci. 2001 Dec 16: 781-3 |
| PMID | 11748362 |
| Title | Apolipoprotein E genotype in Korean schizophrenic patients. |
| Abstract | The apolipoprotein E (APOE) epsilon4 allele is a known risk factor for the development of Alzheimer's disease, however, an association of the APOE genotype with schizophrenia is controversial. We investigated the association in 60 Korean schizophrenic patients and 60 healthy controls. APOE genotypes were identified by reverse hybridization-based line probe assay. There were significant differences in the distribution of APOE genotypes between schizophrenic patients and controls. APOE epsilon2 and epsilon3 allele frequencies in schizophrenic patients were significantly different from those in controls. Our results suggest that APOE alleles seem to be operative in the pathogenesis of schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | J. Korean Med. Sci. 2001 Dec 16: 781-3 |
| PMID | 11748362 |
| Title | Apolipoprotein E genotype in Korean schizophrenic patients. |
| Abstract | The apolipoprotein E (APOE) epsilon4 allele is a known risk factor for the development of Alzheimer's disease, however, an association of the APOE genotype with schizophrenia is controversial. We investigated the association in 60 Korean schizophrenic patients and 60 healthy controls. APOE genotypes were identified by reverse hybridization-based line probe assay. There were significant differences in the distribution of APOE genotypes between schizophrenic patients and controls. APOE epsilon2 and epsilon3 allele frequencies in schizophrenic patients were significantly different from those in controls. Our results suggest that APOE alleles seem to be operative in the pathogenesis of schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Mol. Psychiatry 2001 May 6: 307-10 |
| PMID | 11326299 |
| Title | Schizophrenic women with the APOE epsilon 4 allele have a worse prognosis than those without it. |
| Abstract | The epsilon 4 allele of APOE is generally accepted to be a risk factor in Alzheimer's disease and it has been related to other neuropsychiatric disorders, including schizophrenia. The results of several case-control studies have been inconclusive. To shed more light on this issue we carried out an association study that compared the APOE common variant in a group of 365 schizophrenia patients and 584 controls. We found no differences in the genotype distributions and allele frequencies of patients and controls. In the group of patients, we also analysed the possible influence of the epsilon 4 allele in the clinical variables. The most important findings are that the age at onset (AAO) of epsilon 4+ schizophrenic women, those that have one or two epsilon 4 alleles, is 4 years earlier than that of epsilon 4- women and their risk of suffering a negative syndrome subtype is four times greater. This was not found in schizophrenic men. Our results show that the APOE variant is not a risk factor for developing schizophrenia but that it may modulate its phenotypic expression in a sex-dependent manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Mol. Psychiatry 2001 May 6: 307-10 |
| PMID | 11326299 |
| Title | Schizophrenic women with the APOE epsilon 4 allele have a worse prognosis than those without it. |
| Abstract | The epsilon 4 allele of APOE is generally accepted to be a risk factor in Alzheimer's disease and it has been related to other neuropsychiatric disorders, including schizophrenia. The results of several case-control studies have been inconclusive. To shed more light on this issue we carried out an association study that compared the APOE common variant in a group of 365 schizophrenia patients and 584 controls. We found no differences in the genotype distributions and allele frequencies of patients and controls. In the group of patients, we also analysed the possible influence of the epsilon 4 allele in the clinical variables. The most important findings are that the age at onset (AAO) of epsilon 4+ schizophrenic women, those that have one or two epsilon 4 alleles, is 4 years earlier than that of epsilon 4- women and their risk of suffering a negative syndrome subtype is four times greater. This was not found in schizophrenic men. Our results show that the APOE variant is not a risk factor for developing schizophrenia but that it may modulate its phenotypic expression in a sex-dependent manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Am. J. Med. Genet. 2002 Aug 114: 641-2 |
| PMID | 12210279 |
| Title | Possible effect of the APOE epsilon 4 allele on the hippocampal volume and asymmetry in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Acta Psychiatr Scand 2002 Jan 105: 71-5 |
| PMID | 12086229 |
| Title | Apolipoprotein E genotype and schizophrenia: further negative evidence. |
| Abstract | To investigate the association between apolipoprotein E (APOE) genotype and schizophrenia. We genotyped 106 schizophrenic out-patients [Diagnostic Statistic Manual IV (DSM-IV) criteria] and 250 healthy volunteers (hospital staff and blood donors) from Asturias (Northern Spain). The APOE genotypes (epsilon2, epsilon3, epsilon4-alleles) were determined after polymerase chain reaction (PCR) amplification, followed by digestion with the restriction enzyme Cfol and electrophoresis on a 4% agarose gel. No significant differences in APOE-allele frequencies between patients and controls was found, although an increased 64-frequency was recorded in patients compared with controls [9.0% vs. 6.2%, P = 0.124; odds ratio (OR) = 1.49; 95% confidence interval (CI) = 0.82-2.70]. APOE-genotype frequencies did not differ between both groups. The mean age of onset for schizophrenic patients that carried the epsilon4-allele was not significantly different from that of patients without this allele. Variation in the APOE gene was not associated with the development of schizophrenia in our population. APOE-genotypes did not modify the age of onset of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Acta Psychiatr Scand 2002 Jan 105: 71-5 |
| PMID | 12086229 |
| Title | Apolipoprotein E genotype and schizophrenia: further negative evidence. |
| Abstract | To investigate the association between apolipoprotein E (APOE) genotype and schizophrenia. We genotyped 106 schizophrenic out-patients [Diagnostic Statistic Manual IV (DSM-IV) criteria] and 250 healthy volunteers (hospital staff and blood donors) from Asturias (Northern Spain). The APOE genotypes (epsilon2, epsilon3, epsilon4-alleles) were determined after polymerase chain reaction (PCR) amplification, followed by digestion with the restriction enzyme Cfol and electrophoresis on a 4% agarose gel. No significant differences in APOE-allele frequencies between patients and controls was found, although an increased 64-frequency was recorded in patients compared with controls [9.0% vs. 6.2%, P = 0.124; odds ratio (OR) = 1.49; 95% confidence interval (CI) = 0.82-2.70]. APOE-genotype frequencies did not differ between both groups. The mean age of onset for schizophrenic patients that carried the epsilon4-allele was not significantly different from that of patients without this allele. Variation in the APOE gene was not associated with the development of schizophrenia in our population. APOE-genotypes did not modify the age of onset of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Biol. Psychiatry 2003 Sep 54: 616-22 |
| PMID | 13129656 |
| Title | Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia. |
| Abstract | It is unclear whether altered expression of a specific isoform of apolipoprotein E (APOE) is associated with the pathology of schizophrenia. To address whether APOE may be involved in the pathology of schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann's area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis. The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts. There was a significant increase in the levels of APOE protein in BA 9 from the schizophrenic subjects (Mean +/- SEM: 270 +/- 8.3 vs. 238 +/- 7.1 ng APOE/mg protein, p =.008) and a decrease in tissue from an analogous cortical region from rats treated with haloperidol compared with vehicle-treated animals (50 +/- 6.4 vs. 116 +/- 9.2 ng APOE/mg protein; p =.0002). These data support the hypothesis that increased levels of APOE may be associated with the pathology of schizophrenia and that antipsychotic drugs decrease APOE levels as part of their therapeutic actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Biol. Psychiatry 2003 Sep 54: 616-22 |
| PMID | 13129656 |
| Title | Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia. |
| Abstract | It is unclear whether altered expression of a specific isoform of apolipoprotein E (APOE) is associated with the pathology of schizophrenia. To address whether APOE may be involved in the pathology of schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann's area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis. The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts. There was a significant increase in the levels of APOE protein in BA 9 from the schizophrenic subjects (Mean +/- SEM: 270 +/- 8.3 vs. 238 +/- 7.1 ng APOE/mg protein, p =.008) and a decrease in tissue from an analogous cortical region from rats treated with haloperidol compared with vehicle-treated animals (50 +/- 6.4 vs. 116 +/- 9.2 ng APOE/mg protein; p =.0002). These data support the hypothesis that increased levels of APOE may be associated with the pathology of schizophrenia and that antipsychotic drugs decrease APOE levels as part of their therapeutic actions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Schizophr. Res. 2003 Aug 62: 225-30 |
| PMID | 12837518 |
| Title | Association of APOE gene with schizophrenia in Chinese: a possible risk factor in times of malnutrition. |
| Abstract | Five hundred and seventy nine Chinese patients with schizophrenia who met DSMIV criteria for the disorder were genotyped for alleles epsilon 2,3,4 of apolipoprotein E (APOE) gene. All were recruited from inpatients and outpatients attending a large mental health centre in Shanghai. Results were compared to APOE data on 1528 controls drawn from the same area. Major differences in APOE genotype ratios and allele frequencies were observed between the patients and controls. The patients with schizophrenia had highly significantly (p<0.0001) increased epsilon 4/-genotypes and allele frequencies, and decreased epsilon 3/3 genotypes and epsilon 3 allele frequencies compared to controls. The effect was independent of sex and/or age of onset of illness, but strongly influenced by date of birth. Significant differences were restricted to individuals with schizophrenia born either before 1949 or during the period 1958-1967. Both were times of severe food shortages and malnutrition. We suggest that APOE may operate as an additional risk factor for schizophrenia in individuals subjected to fetal and/or early postnatal malnutrition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 18-23 |
| PMID | 12707932 |
| Title | Apolipoprotein E in schizophrenia: a French association study and meta-analysis. |
| Abstract | schizophrenic disorders are complex genetic disorders that may involve multiple genes of small effect. Apolipoprotein E (APOE) gene variants are associated with alterations in brain function and an increased risk of Alzheimer's disease (AD). However, conflicting results have been reported in schizophrenia. We compared the APOE genotypes of 114 French Caucasian schizophrenic patients and 91 normal controls. No differences in APOE allele or genotype frequencies were observed between the two groups. However, we observed a possible association between male schizophrenic patients and the APOE epsilon 2 epsilon 3 genotype. In addition, a meta-analysis of all published case-control studies on APOE and schizophrenia did not support a major role for APOE gene variants in schizophrenia as a whole. However, APOE may be associated with particular forms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 May 119B: 18-23 |
| PMID | 12707932 |
| Title | Apolipoprotein E in schizophrenia: a French association study and meta-analysis. |
| Abstract | schizophrenic disorders are complex genetic disorders that may involve multiple genes of small effect. Apolipoprotein E (APOE) gene variants are associated with alterations in brain function and an increased risk of Alzheimer's disease (AD). However, conflicting results have been reported in schizophrenia. We compared the APOE genotypes of 114 French Caucasian schizophrenic patients and 91 normal controls. No differences in APOE allele or genotype frequencies were observed between the two groups. However, we observed a possible association between male schizophrenic patients and the APOE epsilon 2 epsilon 3 genotype. In addition, a meta-analysis of all published case-control studies on APOE and schizophrenia did not support a major role for APOE gene variants in schizophrenia as a whole. However, APOE may be associated with particular forms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Neurosci. Lett. 2004 Nov 370: 127-9 |
| PMID | 15488308 |
| Title | Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer Disease. |
| Abstract | There is emerging evidence that psychosis in Alzheimer Disease (AD) represents a clinically relevant phenotype with a distinct biological process. It has been reported that a functional polymorphism of the catechol-O-methyltransferase (COMT) gene predisposes to an increased risk for schizophrenia and likely to psychosis susceptibility. Aim of this study was to evaluate functional COMT genetic variation as a risk factor for psychosis in Alzheimer Disease. One hundred eighty-one AD patients and 208 age-matched controls underwent clinical and neuropsychological examination, behavioural and psychiatric disturbances evaluation, and APOE and COMT genotyping. The distribution of COMT genotypes did not significantly differ in AD compared to controls. Among patients with psychosis (32.6%), 88.1% were COMT*H carriers (COMT H/H or COMT H/L, p < .01). The Odds Ratio (OR) for risk of psychosis in COMT*H carriers was 2.66 (confidence interval, CI 95%: 1.6-6.62), taking into account possible confounding factors. A comparable influence of COMT polymorphism on psychosis over the course of the disease was reported. These findings suggest that COMT polymorphism influences on the risk of psychosis since the early stages, and claims for the possibility to identify distinct phenotypes on genetic basis among AD patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Neurosci. Lett. 2004 Sep 368: 33-6 |
| PMID | 15342129 |
| Title | Psychotic symptoms in Alzheimer's disease are not influenced by polymorphic variation at the dopamine receptor DRD3 gene. |
| Abstract | It has been suggested that genetic influences unmasked during neurodevelopment to produce schizophrenia may appear throughout neurodegeneration to produce AD plus psychosis. Risk of schizophrenia and psychosis in Alzheimer's disease (AD) has been linked to polymorphic variation at the dopamine receptor DRD3 gene implying similar causative mechanisms. We tested this association in a large cohort of Alzheimer's disease patients with a diagnosis of probable AD of 3 years or more duration from the relatively genetically homogenous Northern Irish population. We assessed relationships between genotypes/alleles of the DRD3 BalI polymorphism and the presence or absence of psychotic symptoms (delusions, hallucinations) in AD patients during the month prior to interview and at any stage during the dementia. No significant associations were found when delusions and hallucinations were cross-tabulated against S and G alleles and SS, SG and GG genotypes. Logistic regression failed to detect any influence of APOE, gender, family history or prior psychiatric history. In conclusion, we were unable to confirm previously reported associations between the DRD3 BalI polymorphism and psychotic symptoms in AD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | J. Hum. Genet. 2004 -1 49: 355-9 |
| PMID | 15221639 |
| Title | Apolipoprotein E polymorphism is associated with age of onset in schizophrenia. |
| Abstract | The aims of the study were to investigate the relationship between Apolipoprotein E (APOE) polymorphism, risk of schizophrenia, treatment response to conventional anti-psychotics, and age of onset in schizophrenia. The sample comprised 94 Finnish patients with a DSM-IV diagnosis of schizophrenia. Forty-three of the patients were good responders to conventional anti-psychotics and 51 were classified as non-responders. The control group consisted of 98 healthy blood donors. The APOE allele frequencies (epsilon 2, epsilon 3, and epsilon 4) were 4.8, 72.3, and 22.9% in patients and 7.1, 75.0, and 17.9 in controls. None of the differences between groups were statistically significant. No association between treatment response and APOE genotype was found. Patients with APOE epsilon 4/epsilon 4 genotype had a markedly lower age of onset compared with rest of the sample (p=0.0015), which remained significant when controlling for gender (p=0.02). There was an increasing linear trend between the number of epsilon 3 alleles (0, 1, or 2) and age of onset in schizophrenia (p=0.08). An inverse trend was found between the number of epsilon 4 alleles and age of onset (p=0.07). No relationship between APOE polymorphism and risk for schizophrenia was found. APOE epsilon 4/epsilon 4 genotype may be associated with early onset schizophrenia. APOE epsilon 3 allele may function protectively in later onset in this disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Biol. Psychiatry 2005 Apr 57: 711-5 |
| PMID | 15820227 |
| Title | Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. |
| Abstract | This study extends an initial finding of increased levels of APOE in Brodmann's area (BA) 9 from subjects with schizophrenia to determine if APOE is altered in other brain regions and in brains from subjects with bipolar I disorder (BID). APOE was quantified APOE in BA 9, 10, 40, 46 and caudate putamen from control (n = 18), schizophrenic (n = 19) and BID (n = 8) subjects using Western blotting. In schizophrenia, there was increased APOE in BA9 (mean +/- SEM: schizophrenia 3.8 +/- .18 vs. control 3.2 +/- .19) and BA46 (schizophrenia 2.7 +/- .26 vs. control 1.6 +/- .20). In BID, increased levels of the apolipoprotein were detected in the caudate putamen (BID 3.3 +/- .44 vs. control 2.4 +/- .19) and BA9 (BID 4.0 +/- .27 vs. control 3.2 +/- .19) with a decrease in APOE being measured in BA10 (BID 1.6 +/- .16 vs. control 3.9 +/- .53). This study has shown disease specific, regionally discrete changes in levels of APOE in brain obtained post mortem from schizophrenic and BID subjects. Our data adds weight to the hypothesis that changes in the levels of apolipoproteins may be involved in the pathologies of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Biol. Psychiatry 2005 Apr 57: 711-5 |
| PMID | 15820227 |
| Title | Differential changes in apolipoprotein E in schizophrenia and bipolar I disorder. |
| Abstract | This study extends an initial finding of increased levels of APOE in Brodmann's area (BA) 9 from subjects with schizophrenia to determine if APOE is altered in other brain regions and in brains from subjects with bipolar I disorder (BID). APOE was quantified APOE in BA 9, 10, 40, 46 and caudate putamen from control (n = 18), schizophrenic (n = 19) and BID (n = 8) subjects using Western blotting. In schizophrenia, there was increased APOE in BA9 (mean +/- SEM: schizophrenia 3.8 +/- .18 vs. control 3.2 +/- .19) and BA46 (schizophrenia 2.7 +/- .26 vs. control 1.6 +/- .20). In BID, increased levels of the apolipoprotein were detected in the caudate putamen (BID 3.3 +/- .44 vs. control 2.4 +/- .19) and BA9 (BID 4.0 +/- .27 vs. control 3.2 +/- .19) with a decrease in APOE being measured in BA10 (BID 1.6 +/- .16 vs. control 3.9 +/- .53). This study has shown disease specific, regionally discrete changes in levels of APOE in brain obtained post mortem from schizophrenic and BID subjects. Our data adds weight to the hypothesis that changes in the levels of apolipoproteins may be involved in the pathologies of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | J. Proteome Res. 2006 Nov 5: 3213-6 |
| PMID | 17081074 |
| Title | Dysregulation of retinoid transporters expression in body fluids of schizophrenia patients. |
| Abstract | This study aims to find the biomarkers or associated proteins in body fluids of schizophrenia patients so that we can further understand the etiology of schizophrenia. We applied proteomic technologies combining two-dimensional electrophoresis with Coomassie blue staining and mass spectrometry and identified a procedure for the clinical screening of disease-influenced body fluid proteins in two sets of samples, plasma from 19 schizophrenia patients and cerebrospinal fluid (CSF) from 35 drug-treated schizophrenic patients and 36 healthy controls. The expression of transthyretin (TTR) tetramer increased significantly in plasma of schizophrenic patients after a valid 2 months in-hospital antipsychotic treatment. Conversely, the expression of the TTR tetramer and apolipoprotein E (APOE) was down-regulated by up to 1.68 and 3.62 times, respectively, in the CSF of schizophrenia patients compared to that of normal controls, which has not been reported previously. Considering that the TTR tetramer and APOE are both retinoid transporters, retinoid dysfunction might be involved in the pathology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | J. Proteome Res. 2006 Nov 5: 3213-6 |
| PMID | 17081074 |
| Title | Dysregulation of retinoid transporters expression in body fluids of schizophrenia patients. |
| Abstract | This study aims to find the biomarkers or associated proteins in body fluids of schizophrenia patients so that we can further understand the etiology of schizophrenia. We applied proteomic technologies combining two-dimensional electrophoresis with Coomassie blue staining and mass spectrometry and identified a procedure for the clinical screening of disease-influenced body fluid proteins in two sets of samples, plasma from 19 schizophrenia patients and cerebrospinal fluid (CSF) from 35 drug-treated schizophrenic patients and 36 healthy controls. The expression of transthyretin (TTR) tetramer increased significantly in plasma of schizophrenic patients after a valid 2 months in-hospital antipsychotic treatment. Conversely, the expression of the TTR tetramer and apolipoprotein E (APOE) was down-regulated by up to 1.68 and 3.62 times, respectively, in the CSF of schizophrenia patients compared to that of normal controls, which has not been reported previously. Considering that the TTR tetramer and APOE are both retinoid transporters, retinoid dysfunction might be involved in the pathology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | J Neuropsychiatry Clin Neurosci 2006 -1 18: 231-3 |
| PMID | 16720801 |
| Title | Apolipoprotein E genotype and odor identification in schizophrenia. |
| Abstract | The authors examined Apolipoprotein E (APOE) genotype frequencies and unirhinal odor identification in 28 schizophrenia patients and 26 healthy comparison subjects. No significant associations between APOE status and olfaction were observed in either diagnostic group. The authors concluded that olfactory deficits in schizophrenia do not appear to be mediated by the APOE allele. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Schizophr. Res. 2006 Jun 84: 228-35 |
| PMID | 16567081 |
| Title | Meta-analysis of association between ApoE epsilon4 allele and schizophrenia. |
| Abstract | Several case-control studies have reported an association between schizophrenia and the epsilon4 allele of Apolipoprotein E gene. The results have been equivocal. This meta-analysis has evaluated the collective evidence for an association between the epsilon4 allele of Apolipoprotein E gene and schizophrenia. We analyzed published data sequentially first considering epsilon4 allele itself, and then epsilon4 carrier status as risk factors for schizophrenia using a sample of 17 population-based case-control studies, of which 6 were from Asian and 11 from Caucasian populations. The pooled odds ratios from the Caucasian populations showed a modest association with risk of schizophrenia for epsilon4 allele and epsilon4 carrier genotype. No other alleles or genotypes were significant in either Asian or Caucasian populations when analysed separately or combined, although the sample size had over 80% power to detect a significant odds ratio of 1.9 in Asian-population studies and 1.6 in Caucasian-population studies. After allowing for sensitivity analysis of the studies and assessment of publication bias, we conclude that the epsilon4 allele of Apolipoprotein E does not play a major role in risk of schizophrenia in Caucasian populations. Since significant heterogeneity was present among the 6 Asian populations reported to date, further studies using larger sample sizes are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Eur. J. Hum. Genet. 2006 May 14: 529-34 |
| PMID | 16538225 |
| Title | Use of phenotypic covariates in association analysis by sequential addition of cases. |
| Abstract | Optimal use of phenotype information is important in complex disease gene mapping. We describe a method, sequential addition, for the analysis of case-control data by taking into account of a quantitative trait that is measured in cases but not in controls. The method also provides an estimate of the best phenotype definition for future studies. We demonstrate proof of principle, using an example of incorporation of age-at-onset data into a study of a small sample for association between APOE and late-onset Alzheimer's disease. The sequential addition method finds evidence of association when conventional case-control methods fail. We also illustrate the use of the method for taking account of a dimensional measure of psychosis in a study of the schizophrenia susceptibility gene, dysbindin, in bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2006 Dec 30: 1369-80 |
| PMID | 16793187 |
| Title | Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications. |
| Abstract | Two members of the family of low-density lipoprotein receptors (i.e., very low-density lipoprotein [VLDL] receptor and apolipoprotein E [APOE] type 2 receptor) are expressed in brain, where they bind and transduce reelin, a secreted glycoprotein that shares structural analogies with extracellular matrix proteins. In the developing fetal brain, reelin-signal transduction is critical for the correct positioning of neurons and the formation of appropriate synaptic connections, whereas in the mature brain, reelin participates in the mediation of experience-dependent synaptic plasticity. An important "downstream" consequence of the reelin-signal transduction cascade is inhibition of the phosphorylation of tau, a protein that regulates microtubule assembly and stability. Importantly, hyperphosphorylated tau comprises the paired helical filament, whose pathological deposition as neurofibrillary tangles is implicated in Alzheimer's disease; hyperphosphorylated tau is also implicated in the pathogenesis of other neurodegenerative disorders. Isoforms of APOE may affect the binding of reelin to its cell surface receptors and, thereby, influence tau phosphorylation, whereas insulin, insulin-like growth factor-1, and the lithium ion have actions within the cell at the level of the specific tyrosine kinases involved in the phosphorylation of tau. These data support the exploration of pharmacotherapeutic interventions designed to prevent or reduce the burden of hyperphosphorylated tau. Impaired reelin-signal transduction due to an actual deficiency of reelin expression may occur in at least some patients with psychotic disorders, especially schizophrenia; conceivably, hyperphosphorylation of tau would result from deficient transduction of reelin in schizophrenia. schizophrenia has been conceptualized as a neurodevelopmental disorder of impaired synaptic "connectivity", whose consequence does not become fully apparent until late adolescence or early adulthood. In summary, hyperphosphorylation of tau may be an underlying point of pathological convergence for several neuropsychiatric disorders, and prevention of tau hyperphosphorylation may be an important therapeutic target. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Mov. Disord. 2006 Apr 21: 540-2 |
| PMID | 16261623 |
| Title | APOE2 allele increased in tardive dyskinesia. |
| Abstract | Ninety-seven inpatients with tardive dyskinesia (average AIMS score = 13), the majority of whom were schizophrenic, were studied. Forty patients were Caucasian, and 57 were African-American. The APOE genotypes of these patients were compared to previously published genotypes of controls and with previously published studies of APOE genotypes in patients with schizophrenia. There were no significant differences in APOE allele frequencies comparing the African-American tardive dyskinesia population and the African-American control groups. In contrast, significant (< 0.05) P values were obtained comparing the Caucasian tardive dyskinesia population to the Caucasian controls, when comparing allele frequencies and genotypic frequencies. This study suggests that Caucasians bearing an APOE2 allele are at increased risk of developing tardive dyskinesia, whereas African-Americans are not. APOE genotype-specific risks of both tardive dyskinesia and Alzheimer's disease that vary across populations could be due to recruitment of patients or controls or could be due to modifying effects of differing genetic or environmental backgrounds. The mechanism by which the APOE2 allele increases risk of tardive dyskinesia is not known. Further information about the mechanisms of increased risk of tardive dyskinesia could result in stratification of prescribing practices weighing the costs of medications against the relative risk of side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Mov. Disord. 2006 Apr 21: 540-2 |
| PMID | 16261623 |
| Title | APOE2 allele increased in tardive dyskinesia. |
| Abstract | Ninety-seven inpatients with tardive dyskinesia (average AIMS score = 13), the majority of whom were schizophrenic, were studied. Forty patients were Caucasian, and 57 were African-American. The APOE genotypes of these patients were compared to previously published genotypes of controls and with previously published studies of APOE genotypes in patients with schizophrenia. There were no significant differences in APOE allele frequencies comparing the African-American tardive dyskinesia population and the African-American control groups. In contrast, significant (< 0.05) P values were obtained comparing the Caucasian tardive dyskinesia population to the Caucasian controls, when comparing allele frequencies and genotypic frequencies. This study suggests that Caucasians bearing an APOE2 allele are at increased risk of developing tardive dyskinesia, whereas African-Americans are not. APOE genotype-specific risks of both tardive dyskinesia and Alzheimer's disease that vary across populations could be due to recruitment of patients or controls or could be due to modifying effects of differing genetic or environmental backgrounds. The mechanism by which the APOE2 allele increases risk of tardive dyskinesia is not known. Further information about the mechanisms of increased risk of tardive dyskinesia could result in stratification of prescribing practices weighing the costs of medications against the relative risk of side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | J. Alzheimers Dis. 2007 Aug 12: 73-92 |
| PMID | 17851196 |
| Title | Genetics of Alzheimer's disease. A rapidly evolving field. |
| Abstract | Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Schizophr. Res. 2008 Mar 100: 308-15 |
| PMID | 18164902 |
| Title | Analyses of variants located in estrogen metabolism genes (ESR1, ESR2, COMT and APOE) and schizophrenia. |
| Abstract | Relationships between gender, age-of-onset of schizophrenia and reproductive age strongly suggest a key role for gonadal hormones, and more specifically for estrogens, in the etiology of the illness. Also, estrogens act as neural growth and trophic factors influencing neuron and glial cells in many areas of the central nervous system. Therefore, we investigated the association between schizophrenia and 4 genes related to estrogen metabolism. These genes are ESR1 (estrogen receptor 1), ESR2 (estrogen receptor 2), APOE (apolipoprotein E) and COMT (catechol-O-methyltransferase). The expression of APOE and COMT, which contain estrogen response elements, have been demonstrated to be regulated by the estrogen receptors. In this current association study, we examined 59 single nucleotide polymorphisms (SNPs) located in the ESR1 (26), ESR2 (14), APOE (7) and COMT (12) loci. Allele frequencies were evaluated in the schizophrenia (n=585)-control (n=615) sample and no association was found with any of the four genes. In conclusion, our data suggest that the four analyzed genes do not play an important role in susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Ann. N. Y. Acad. Sci. 2008 -1 1129: 200-12 |
| PMID | 18591481 |
| Title | Molecular genetics of attention. |
| Abstract | The sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-epsilon4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Nat. Genet. 2008 Jul 40: 827-34 |
| PMID | 18583979 |
| Title | Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. |
| Abstract | In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | 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 of schizophrenia and 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, schizophrenic, schizophrenics |
| 37 | Schizophr Bull 2009 Nov 35: 1163-82 |
| PMID | 18552348 |
| Title | Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii. |
| Abstract | Many genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | J Neuropsychiatry Clin Neurosci 2009 -1 21: 440-4 |
| PMID | 19996253 |
| Title | APOE-epsilon3 and APOE-219G haplotypes increase the risk for schizophrenia in sibling pairs. |
| Abstract | To investigate the role of the apolipoprotein E (APOE) gene in schizophrenia, the authors analyzed 60 families with this mental disorder. An association in the presence of linkage test (APL) and haplotypes analysis were undertaken using the APL v1.1 software. A global allelic transmitted was significant for APOE-epsilon3 (chi(2)=6.24, p=0.01); this allele is mainly carried by female patients (chi(2)=8.33, p=0.003), whereas APOE-219G is preferentially transmitted in males (p=0.02). Furthermore, our results show that haplotypes APOE-epsilon3/APOE-219G are associated with schizophrenia (chi(2)=11.61, p=0.01). These results provide evidence that the APOE gene may play a significant role in the etiology of schizophrenia in the Mexican population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Neuropsychobiology 2009 -1 60: 67-72 |
| PMID | 19752580 |
| Title | Apolipoprotein E polymorphism and clinical disease phenotypes in Arab patients with schizophrenia. |
| Abstract | Apolipoprotein E (APOE) is polymorphic, and may be involved in the pathogenesis and clinical expression of schizophrenia. This study aimed to investigate the frequency of specific APOE genotypes and alleles in a schizophrenic Arab population and evaluate the association of specific APOE types with clinical phenotypes of the disease. Two age-matched groups of subjects were studied: (1) healthy controls, n = 165; (2) patients with schizophrenia (SZ), n = 207. Each subject was evaluated for age and mode of onset of disease, family history of psychosis, disease severity and outcome over the years of illness. APOE genotyping was performed by a validated PCR-RFLP technique. Genotype E3E2 and allele E2 were less frequent in the patients with schizophrenia (p = 0.04), and both APOE types tended to be more common in male than female schizophrenic patients (p = 0.08). schizophrenic patients with a positive family history of psychosis had lower frequencies of genotype E3E2 and allele E2 (both p = 0.04). Genotype E3E4 and allele E4 were least common in patients with an age at onset of disease >31 years (OR: 5.5, 95% CI: 1.1-27.4), particularly in males. APOE genetic polymorphism potentially influences susceptibility to schizophrenia and may be associated with aspects of its phenotypic expression, particularly gender, age of onset and family history of psychotic illness. This relationship of APOE with schizophrenia is likely to be race- and gender-specific. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Neuropsychobiology 2009 -1 60: 67-72 |
| PMID | 19752580 |
| Title | Apolipoprotein E polymorphism and clinical disease phenotypes in Arab patients with schizophrenia. |
| Abstract | Apolipoprotein E (APOE) is polymorphic, and may be involved in the pathogenesis and clinical expression of schizophrenia. This study aimed to investigate the frequency of specific APOE genotypes and alleles in a schizophrenic Arab population and evaluate the association of specific APOE types with clinical phenotypes of the disease. Two age-matched groups of subjects were studied: (1) healthy controls, n = 165; (2) patients with schizophrenia (SZ), n = 207. Each subject was evaluated for age and mode of onset of disease, family history of psychosis, disease severity and outcome over the years of illness. APOE genotyping was performed by a validated PCR-RFLP technique. Genotype E3E2 and allele E2 were less frequent in the patients with schizophrenia (p = 0.04), and both APOE types tended to be more common in male than female schizophrenic patients (p = 0.08). schizophrenic patients with a positive family history of psychosis had lower frequencies of genotype E3E2 and allele E2 (both p = 0.04). Genotype E3E4 and allele E4 were least common in patients with an age at onset of disease >31 years (OR: 5.5, 95% CI: 1.1-27.4), particularly in males. APOE genetic polymorphism potentially influences susceptibility to schizophrenia and may be associated with aspects of its phenotypic expression, particularly gender, age of onset and family history of psychotic illness. This relationship of APOE with schizophrenia is likely to be race- and gender-specific. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Eur. Psychiatry 2009 Oct 24: 456-63 |
| PMID | 19541455 |
| Title | Apolipoprotein-E gene variants associated with cardiovascular risk factors in antipsychotic recipients. |
| Abstract | Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of APOE found in specific areas of post-mortem schizophrenic brains. This study investigated whether APOE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Int. J. Neurosci. 2010 Jul 120: 502-6 |
| PMID | 20583903 |
| Title | Schizophrenia and apolipoprotein E gene polymorphism in Serbian population. |
| Abstract | Apolipoprotein E (APOE) gene variants are associated with alterations in brain function and increased risk of Alzheimer's disease (AD) and conflicting results have been reported in schizophrenia. Our results showed no significant differences in APOE allele or genotype frequencies between the Serbian schizophrenic patients and control individuals. However, we observed a possible association between particular subtypes of schizophrenia and APOE epsilon3/epsilon3 genotype (p = .01221) and epsilon4 allele showed a tendency toward positive association with responding to typical neuroleptics. APOE genotypes have no major influence on risk of schizophrenia, treatment and response to conventional antipsychotics, and age of onset in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Int. J. Neurosci. 2010 Jul 120: 502-6 |
| PMID | 20583903 |
| Title | Schizophrenia and apolipoprotein E gene polymorphism in Serbian population. |
| Abstract | Apolipoprotein E (APOE) gene variants are associated with alterations in brain function and increased risk of Alzheimer's disease (AD) and conflicting results have been reported in schizophrenia. Our results showed no significant differences in APOE allele or genotype frequencies between the Serbian schizophrenic patients and control individuals. However, we observed a possible association between particular subtypes of schizophrenia and APOE epsilon3/epsilon3 genotype (p = .01221) and epsilon4 allele showed a tendency toward positive association with responding to typical neuroleptics. APOE genotypes have no major influence on risk of schizophrenia, treatment and response to conventional antipsychotics, and age of onset in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Front Psychiatry 2010 -1 1: 19 |
| PMID | 21423430 |
| Title | Low Density Lipoprotein Receptor-Related Protein and Apolipoprotein E Expression is Altered in Schizophrenia. |
| Abstract | Our recent microarray study reported altered mRNA expression of several low density lipoprotein receptor-related proteins (LRP) associated with the first 4 years following diagnosis with schizophrenia. Whilst this finding is novel, apolipoprotein E (APOE), which mediates its activity through LRPs, has been reported by several studies to be altered in brains of subjects with schizophrenia. We used qPCR to measure the expression of LRP2, LRP4, LRP6, LRP8, LRP10 and LRP12 mRNA in Brodmann's area (BA) 46 of the dorsolateral prefrontal cortex in 15 subjects with short duration of illness schizophrenia (SDS) and 15 pair matched controls. We also used Western blotting to measure APOE protein expression in BA46 from these subjects. Amongst the LRPs examined, LRP10 expression was significantly increased (P?=?0.03) and LRP12 was significantly decreased (P?APOE protein expression was also increased in SDS (P?=?0.01). No other marker examined in this study was altered with diagnosis. Our data supports a role for distinct members of the LRP family in the pathology of schizophrenia and adds weight to the hypothesis that aberrant apolipoprotein signaling is involved in the early stages of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Schizophr. Res. 2010 Jan 116: 90-6 |
| PMID | 19896333 |
| Title | Cortical neuritic plaques and hippocampal neurofibrillary tangles are related to dementia severity in elderly schizophrenia patients. |
| Abstract | Cognitive decline has been described in elderly patients with schizophrenia, but the underlying pathology remains unknown. Some studies report increases in plaques and neurofibrillary tangles, but there is no evidence for an increased risk for Alzheimer's disease (AD) in elderly schizophrenics. Models of a decreased cerebral reserve suggest that increases in AD-related neuropathology below the threshold for a neuropathological diagnosis could be related to dementia severity in elderly schizophrenia patients. We tested this hypothesis in 110 autopsy specimens of schizophrenia patients, without a neuropathological diagnosis of AD or other neurodegenerative disorders. Furthermore, we assessed the effects of apolipoprotein E (APOE) status, a known genetic risk factor for AD. Measures of density of neuritic plaques were obtained in five cortical regions, and the degree of hippocampal neurofibrillary tangles was rated. Dementia severity was measured prior to postmortem using the Clinical Dementia Rating (CDR) scale. multivariate analyses of variance were conducted with the factors dementia severity, by APOE4 carrier status. Hippocampal neurofibrillary tangles correlated with increased dementia severity (p<.05). Neuritic plaque density increased with greater dementia severity (p<.005), and APOE4 carrier status (p<.005), and these differences were magnified by the APOE4 carrier status (p<.01). Even below the threshold for a neuropathological diagnosis of AD, neuritic plaques and hippocampal neurofibrillary tangles are associated with dementia severity in schizophrenia patients, even more so in the presence of genetic risk factors, suggesting that a decreased cerebral reserve in elderly schizophrenics may increase susceptibility for dementia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Schizophr. Res. 2010 Jan 116: 90-6 |
| PMID | 19896333 |
| Title | Cortical neuritic plaques and hippocampal neurofibrillary tangles are related to dementia severity in elderly schizophrenia patients. |
| Abstract | Cognitive decline has been described in elderly patients with schizophrenia, but the underlying pathology remains unknown. Some studies report increases in plaques and neurofibrillary tangles, but there is no evidence for an increased risk for Alzheimer's disease (AD) in elderly schizophrenics. Models of a decreased cerebral reserve suggest that increases in AD-related neuropathology below the threshold for a neuropathological diagnosis could be related to dementia severity in elderly schizophrenia patients. We tested this hypothesis in 110 autopsy specimens of schizophrenia patients, without a neuropathological diagnosis of AD or other neurodegenerative disorders. Furthermore, we assessed the effects of apolipoprotein E (APOE) status, a known genetic risk factor for AD. Measures of density of neuritic plaques were obtained in five cortical regions, and the degree of hippocampal neurofibrillary tangles was rated. Dementia severity was measured prior to postmortem using the Clinical Dementia Rating (CDR) scale. multivariate analyses of variance were conducted with the factors dementia severity, by APOE4 carrier status. Hippocampal neurofibrillary tangles correlated with increased dementia severity (p<.05). Neuritic plaque density increased with greater dementia severity (p<.005), and APOE4 carrier status (p<.005), and these differences were magnified by the APOE4 carrier status (p<.01). Even below the threshold for a neuropathological diagnosis of AD, neuritic plaques and hippocampal neurofibrillary tangles are associated with dementia severity in schizophrenia patients, even more so in the presence of genetic risk factors, suggesting that a decreased cerebral reserve in elderly schizophrenics may increase susceptibility for dementia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Front Biosci (Landmark Ed) 2011 -1 16: 962-79 |
| PMID | 21196212 |
| Title | The neurobiology of APOE in schizophrenia and mood disorders. |
| Abstract | APOE is a major component of several lipoproteins. In addition to its role as a lipid transport protein APOE also serves a dual role as a glial derived, synaptic signalling molecule and thought to play an important role in synaptic plasticity and cognition. Polymorphisms within the APOE gene have been associated with the incidence of Alzheimer's disease. In light of the similarities in the cognitive deficits experienced in both Alzheimer's disease and schizophrenia as well as the comorbidity of depression in Alzheimer's disease, aberrant APOE signalling has been implicated in the pathologies of schizophrenia and mood disorders. The schizophrenia candidate gene, reelin, also shares common receptors with APOE, further supporting a role for APOE in the pathology of these disorders. This review will summarise the current understanding of the involvement of APOE and its receptors in the symptomatology and pathology of schizophrenia and mood disorders and the implications of this involvement for drug treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | J Psychiatry Neurosci 2011 Jan 36: 47-55 |
| PMID | 20964956 |
| Title | ApoE and cholesterol in schizophrenia and bipolar disorder: comparison of grey and white matter and relation with APOE genotype. |
| Abstract | Apolipoprotein E (APOE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and APOE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between APOE and cholesterol levels and the APOE genotype. We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas APOE was measured by enzyme-linked immunosorbent assay. We found no significant differences in cholesterol or APOE levels among the groups. APOE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between APOE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, APOE levels were significantly higher in APOE ?2 carriers compared with APOE ?3 or APOE ?4 carriers, with cholesterol levels following the opposite trend. LIMITATIONS of our study include our inability to control for potential confounding variables and the small numbers of APOE ?2 and ?4 carriers in each group. Although large amounts of cholesterol are present in white matter, APOE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and APOE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Mol. Psychiatry 2011 Jan 16: 37-58 |
| PMID | 19935739 |
| Title | Identification of blood biomarkers for psychosis using convergent functional genomics. |
| Abstract | There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, APOE, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Gene 2012 Sep 506: 135-40 |
| PMID | 22771913 |
| Title | Role of the apolipoprotein E and catechol-O-methyltransferase genes in prospective and retrospective memory traits. |
| Abstract | Human memory is a complex neurocognitive process. By combining psychological and molecular genetics expertise, we examined the APOE ?4 allele, a known risk factor for Alzheimer's disease, and the COMT Val 158 polymorphism, previously implicated in schizophrenia, for association with lowered memory functioning in healthy adults. To assess memory type we used a range of memory tests of both retrospective and prospective memory. Genotypes were determined using RFLP analysis and compared with mean memory scores using univariate ANOVAs. Despite a modest sample size (n=197), our study found a significant effect of the APOE ?4 polymorphism in prospective memory. Supporting our hypothesis, a significant difference was demonstrated between genotype groups for means of the Comprehensive Assessment of Prospective Memory total score (p=0.036; ?4 alleles=1.99; all other alleles=1.86). In addition, we demonstrate a significant interactive effect between the APOE ?4 and COMT polymorphisms in semantic memory. This is the first study to investigate both APOE and COMT genotypes in relation to memory in non-pathological adults and provides important information regarding the effect of genetic determinants on human memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Transl Psychiatry 2012 -1 2: e173 |
| PMID | 23092977 |
| Title | Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. |
| Abstract | The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Transl Psychiatry 2012 -1 2: e173 |
| PMID | 23092977 |
| Title | Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. |
| Abstract | The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Transl Psychiatry 2012 -1 2: e173 |
| PMID | 23092977 |
| Title | Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. |
| Abstract | The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Front Psychiatry 2012 -1 3: 32 |
| PMID | 22529823 |
| Title | Connectomic intermediate phenotypes for psychiatric disorders. |
| Abstract | Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 392-404 |
| PMID | 22419519 |
| Title | Impact of the Reelin signaling cascade (ligands-receptors-adaptor complex) on cognition in schizophrenia. |
| Abstract | Our previous neurocognitive studies of schizophrenia outlined two clusters of affected subjects--cognitively spared (CS) and cognitive deficit (CD), the latter's characteristics pointing to developmental origins and impaired synaptic plasticity. Here we investigate the contribution of polymorphisms in major regulators of these processes to susceptibility to schizophrenia and to CD in patients. We examine variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1. Association analysis with disease outcome and cognitive performance in the Western Australian Family Study of schizophrenia (WAFSS) was followed by replication analysis in the Australian schizophrenia Research Bank (ASRB) and in the Health in Men Study (HIMS) of normal aging males. In the WAFSS sample, we observed significant association of APOE, APOER2, VLDLR, and DAB1 SNPs with disease outcome in the case-control and CD-control datasets, and with pre-morbid intelligence and verbal memory in cases. HIMS replication analysis supported rs439401 (APOE regulatory region), and rs2297660 and rs3737983 (APOER2), with an effect on memory performance in normal aging subjects consistent with the findings in schizophrenia cases. APOER2 gene expression analysis revealed lower transcript levels in lymphoblastoid cells from cognitively impaired schizophrenia patients of the alternatively spliced exon 19, mediating Reelin signaling and synaptic plasticity in the adult brain. ASRB replication analysis produced marginally significant results, possibly reflecting a recruitment strategy biased toward CS patients. The data suggest a contribution of neurodevelopmental/synaptic plasticity genes to cognitive impairment in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | Psychiatr Q 2012 Jun 83: 127-44 |
| PMID | 21863346 |
| Title | Is there evidence for late cognitive decline in chronic schizophrenia? |
| Abstract | schizophrenia (SZP) has been historically referred to as "dementia praecox" because of the recognition that its onset is associated with deficits in memory, attention and visuospatial orientation. We wondered whether there is evidence for additional cognitive decline late in the course of chronic SZP. This review examined the evidence (1) for cognitive decline late in the course of chronic SZP, (2) for how often the late cognitive decline occurs, and (3) whether the cognitive decline in late-life SZP is related to pathophysiology of SZP versus the superimposition of another type of dementia. A PUBMED search was performed combining the MESH terms schizophrenia and dementia, cognitive decline, cognitive impairment and cognitive deficits. A manual search of article bibliographies was also performed. We included longitudinal clinical studies employing standard tests of cognition. Cross-sectional studies and those that did not test cognition through standard cognitive tests were excluded. The initial search produced 3898 studies. Employing selection criteria yielded twenty-three studies. Our data extraction tool included the number of patients in the study, whether a control group was present, the age of patients at baseline and follow-up, the study setting (inpatients versus outpatients), the cognitive tests employed, study duration, and results. Only three longitudinal studies tested for dementia using Diagnostic and statistical manual of mental disorder (DSM) or International classification of disease (ICD) criteria and compared them to controls: two studies demonstrated an increase in the prevalence of dementia and one did not. Twenty longitudinal studies tested for one or more cognitive domains without employing standard criteria for dementia: twelve studies demonstrated a heterogeneous pattern of cognitive decline and eight did not. Studies generally did not control for known risk factors for cognitive impairment such as education, vascular risk factors, apolipoprotein (APOE) genotype and family history. The evidence for late cognitive decline in SZP is mixed, but, slightly more studies suggest that it occurs. If it occurs, it is unclear whether it is related to SZP or other risks for cognitive impairment. Hence, prospective, longitudinal, controlled studies are needed to confirm that there is progressive cognitive decline in chronic SZP which occurs independent of other risk factors for cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | ISRN Psychiatry 2013 -1 2013: 620361 |
| PMID | 23738220 |
| Title | Chronic phencyclidine increases synapsin-1 and synaptic adaptation proteins in the medial prefrontal cortex. |
| Abstract | Phencyclidine (PCP) mimics many aspects of schizophrenia, yet the underlying mechanism of neurochemical adaptation for PCP is unknown. We therefore used proteomics to study changes in the medial prefrontal cortex in animals with PCP-induced behavioural deficits. Male Wistar rats were injected with saline or 5?mg/kg phencyclidine for 5 days followed by two days of washout. Spontaneous alternation behaviour was tested in a Y-maze and then proteins were extracted from the medial prefrontal cortex. 2D-DIGE analysis followed by spot picking and protein identification with mass spectrometry then provided a list of differentially expressed proteins. Treatment with 5?mg/kg phencyclidine decreased the percentage of correct alternations in the Y-maze compared to saline-treated controls. Proteomics analysis of the medial prefrontal cortex found upregulation of 6 proteins (synapsin-1, Dpysl3, Aco2, Fscn1, Tuba1c, and Mapk1) and downregulation of 11 (Bin1, Dpysl2, Sugt1, APOE, Psme1, ERp29, Pgam1, Uchl1, Ndufv2, Pcmt1, and Vdac1). A trend to upregulation was observed for Gnb4 and Capza2, while downregulation trends were noted for alpha-enolase and Fh. Many of the hits in this study concur with recent postmortem data from schizophrenic patients and this further validates the use of phencyclidine in preclinical translational research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | ISRN Psychiatry 2013 -1 2013: 620361 |
| PMID | 23738220 |
| Title | Chronic phencyclidine increases synapsin-1 and synaptic adaptation proteins in the medial prefrontal cortex. |
| Abstract | Phencyclidine (PCP) mimics many aspects of schizophrenia, yet the underlying mechanism of neurochemical adaptation for PCP is unknown. We therefore used proteomics to study changes in the medial prefrontal cortex in animals with PCP-induced behavioural deficits. Male Wistar rats were injected with saline or 5?mg/kg phencyclidine for 5 days followed by two days of washout. Spontaneous alternation behaviour was tested in a Y-maze and then proteins were extracted from the medial prefrontal cortex. 2D-DIGE analysis followed by spot picking and protein identification with mass spectrometry then provided a list of differentially expressed proteins. Treatment with 5?mg/kg phencyclidine decreased the percentage of correct alternations in the Y-maze compared to saline-treated controls. Proteomics analysis of the medial prefrontal cortex found upregulation of 6 proteins (synapsin-1, Dpysl3, Aco2, Fscn1, Tuba1c, and Mapk1) and downregulation of 11 (Bin1, Dpysl2, Sugt1, APOE, Psme1, ERp29, Pgam1, Uchl1, Ndufv2, Pcmt1, and Vdac1). A trend to upregulation was observed for Gnb4 and Capza2, while downregulation trends were noted for alpha-enolase and Fh. Many of the hits in this study concur with recent postmortem data from schizophrenic patients and this further validates the use of phencyclidine in preclinical translational research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Psychiatr Q 2014 Dec 85: 487-96 |
| PMID | 25085446 |
| Title | No change of the lipid profile under the control of ApoE gene polymorphism in schizophrenics under paliperidone treatment. |
| Abstract | The present study tried to explore the effects of Paliperidone on the lipid profiles of schizophrenia patients. One hundred twenty-nine subjects diagnosed with schizophrenia were enrolled into this study and completed the lipid profile evaluation. Their blood samples were obtained on the morning following a 12-hours fast. Cholesterol and triglyceride (TG) levels in plasma were determined, and lipoproteins were determined by enzymatic methods. All participants provided written informed consent, and underwent additional venous blood withdrawal for DNA extraction for genetic study of the APOE gene polymorphism. Under T test, TC, TG and HDL levels all declined after Paliperidone treatment although with no statistically significant difference. The ratios of TC/HDL declined after Paliperidone treatment, but without statistically significant difference. After GEE-I analysis, we found that APOE4 genotype (? = 34.471; p < 0.001) had a positive effect on the total cholesterol (TC) level; female had positive effect on the high-density lipoprotein (HDL) level (? = 15.361; p = 0.003); and age had a positive effect on the TG level (? = 1.317; p = 0.030). Smoking (? = 0.961; p = 0.016) had a positive effect on the ratio of TC/HDL change. Lipid profiles were not increased after Paliperidone treatment under the control of APOE gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | Psychiatr Q 2014 Dec 85: 487-96 |
| PMID | 25085446 |
| Title | No change of the lipid profile under the control of ApoE gene polymorphism in schizophrenics under paliperidone treatment. |
| Abstract | The present study tried to explore the effects of Paliperidone on the lipid profiles of schizophrenia patients. One hundred twenty-nine subjects diagnosed with schizophrenia were enrolled into this study and completed the lipid profile evaluation. Their blood samples were obtained on the morning following a 12-hours fast. Cholesterol and triglyceride (TG) levels in plasma were determined, and lipoproteins were determined by enzymatic methods. All participants provided written informed consent, and underwent additional venous blood withdrawal for DNA extraction for genetic study of the APOE gene polymorphism. Under T test, TC, TG and HDL levels all declined after Paliperidone treatment although with no statistically significant difference. The ratios of TC/HDL declined after Paliperidone treatment, but without statistically significant difference. After GEE-I analysis, we found that APOE4 genotype (? = 34.471; p < 0.001) had a positive effect on the total cholesterol (TC) level; female had positive effect on the high-density lipoprotein (HDL) level (? = 15.361; p = 0.003); and age had a positive effect on the TG level (? = 1.317; p = 0.030). Smoking (? = 0.961; p = 0.016) had a positive effect on the ratio of TC/HDL change. Lipid profiles were not increased after Paliperidone treatment under the control of APOE gene polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Curr Genet Med Rep 2014 Mar 2: 30-38 |
| PMID | 24883238 |
| Title | Genetics of Psychosis in Alzheimer Disease. |
| Abstract | Psychosis occurs in approximately half of patients with Alzheimer disease (AD with psychosis, AD+P). AD+P patients have more rapid cognitive decline, greater behavioral symptoms, and higher mortality than do AD patients without psychosis. Studies in three independent cohorts have shown that psychosis in AD aggregates in families, with estimated heritability of 29.5 - 60.8%. These findings have motivated studies to investigate and uncover the genes responsible for the development of psychosis, with the ultimate goal of identifying potential biologic mechanisms that may serve as leads to specific therapies. Linkage analyses have implicated loci on chromosomes 2, 6, 7, 8, 15, and 21 with AD+P. Association studies of APOE do not support it as a risk gene for psychosis in AD. No other candidate genes, such as neurodegenerative and monoamine genes, show conclusive evidence of association with AD+P. However, a recent genome-side association study has produced some promising leads, including among them genes that have been associated with schizophrenia. This review summarizes the current knowledge of the genetic basis of AD+P. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | Cereb. Cortex 2014 May 24: 1230-46 |
| PMID | 23283688 |
| Title | Common variants in psychiatric risk genes predict brain structure at birth. |
| Abstract | Studies in adolescents and adults have demonstrated that polymorphisms in putative psychiatric risk genes are associated with differences in brain structure, but cannot address when in development these relationships arise. To determine if common genetic variants in disrupted-in-schizophrenia-1 (DISC1; rs821616 and rs6675281), catechol-O-methyltransferase (COMT; rs4680), neuregulin 1 (NRG1; rs35753505 and rs6994992), apolipoprotein E (APOE; ?3?4 vs. ?3?3), estrogen receptor alpha (ESR1; rs9340799 and rs2234693), brain-derived neurotrophic factor (BDNF; rs6265), and glutamate decarboxylase 1 (GAD1; rs2270335) are associated with individual differences in brain tissue volumes in neonates, we applied both automated region-of-interest volumetry and tensor-based morphometry to a sample of 272 neonates who had received high-resolution magnetic resonance imaging scans. ESR1 (rs9340799) predicted intracranial volume. Local variation in gray matter (GM) volume was significantly associated with polymorphisms in DISC1 (rs821616), COMT, NRG1, APOE, ESR1 (rs9340799), and BDNF. No associations were identified for DISC1 (rs6675281), ESR1 (rs2234693), or GAD1. Of note, neonates homozygous for the DISC1 (rs821616) serine allele exhibited numerous large clusters of reduced GM in the frontal lobes, and neonates homozygous for the COMT valine allele exhibited reduced GM in the temporal cortex and hippocampus, mirroring findings in adults. The results highlight the importance of prenatal brain development in mediating psychiatric risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | Mol. Psychiatry 2014 Oct 19: 1143-9 |
| PMID | 23999527 |
| Title | Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. |
| Abstract | In 2007, a multifaceted syndrome, associated with anti-NMDA receptor autoantibodies (NMDAR-AB) of immunoglobulin-G isotype, has been described, which variably consists of psychosis, epilepsy, cognitive decline and extrapyramidal symptoms. Prevalence and significance of NMDAR-AB in complex neuropsychiatric disease versus health, however, have remained unclear. We tested sera of 2817 subjects (1325 healthy, 1081 schizophrenic, 263 Parkinson and 148 affective-disorder subjects) for presence of NMDAR-AB, conducted a genome-wide genetic association study, comparing AB carriers versus non-carriers, and assessed their influenza AB status. For mechanistic insight and documentation of AB functionality, in vivo experiments involving mice with deficient blood-brain barrier (APOE(-/-)) and in vitro endocytosis assays in primary cortical neurons were performed. In 10.5% of subjects, NMDAR-AB (NR1 subunit) of any immunoglobulin isotype were detected, with no difference in seroprevalence, titer or in vitro functionality between patients and healthy controls. Administration of extracted human serum to mice influenced basal and MK-801-induced activity in the open field only in APOE(-/-) mice injected with NMDAR-AB-positive serum but not in respective controls. Seropositive schizophrenic patients with a history of neurotrauma or birth complications, indicating an at least temporarily compromised blood-brain barrier, had more neurological abnormalities than seronegative patients with comparable history. A common genetic variant (rs524991, P=6.15E-08) as well as past influenza A (P=0.024) or B (P=0.006) infection were identified as predisposing factors for NMDAR-AB seropositivity. The >10% overall seroprevalence of NMDAR-AB of both healthy individuals and patients is unexpectedly high. Clinical significance, however, apparently depends on association with past or present perturbations of blood-brain barrier function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Schizophr. Res. 2015 Dec 169: 355-68 |
| PMID | 26372448 |
| Title | No association between ApoE and schizophrenia: Evidence of systematic review and updated meta-analysis. |
| Abstract | schizophrenia affects between 0.3% and 2% of the worldwide population. A genetic contribution has been postulated in the development of this disorder. Genes such as APOE have been implicated in the neurodevelopment associated with schizophrenia in case-control and meta-analysis studies, but the results remain inconclusive. Due to this, the aim of the present study was to explore the association between APOE and schizophrenia through a meta-analysis. We collected all relevant studies by searching PubMed and EBSCO databases. The pooled odds ratios with 95% confidence intervals were calculated to estimate the association. The following models were evaluated: A) ?4 vs ?3, B) ?4 vs ?2, C) ?4 vs ?3+?2, D) Caucasian population and E) Asian population. Statistical analyses were performed using EPIDAT 3.1 software. The meta-analyses comprised 28 association studies, which included 4703 controls and 3452 subjects with schizophrenia. A significant protective effect was found for allele ?3 in the Asian population (OR=0.73, 95% CI=0.54-0.98). No significant associations were observed in the other models and populations analyzed. Our meta-analysis suggests a protective association between APOE allele ?3 and schizophrenia in the Asian population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Proteomics 2015 Sep 15: 2895-7 |
| PMID | 26331911 |
| Title | A Long Journey from Childhood to Senility: The 23rd HUPO BPP Workshop: 16-17 April 2015, São Paulo, Brazil. |
| Abstract | The HUPO Brain Proteome Project (HUPO BPP) held its 23rd workshop in São Paulo, Brazil, April 16-17, 2015. The focus of the spring workshop was on strategies and predictive therapies concerning neurodegenerative diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Methods Mol. Biol. 2015 -1 1253: 71-93 |
| PMID | 25403528 |
| Title | Epistasis in the risk of human neuropsychiatric disease. |
| Abstract | Neuropsychiatric disease represents the ideal class of disease to assess the role of epistasis, as more genes are expressed in the brain than in any other tissue. In this chapter, two well-studied neuropsychiatric diseases are examined, Alzheimer's disease (AD) and schizophrenia, which have been shown to have multiple and, often, replicated interactions that associate with clinical endpoints or related phenotypes. In each case, a single gene is represented in a plurality of epistatic interactions, apolipoprotein E (APOE) for AD and catechol-O-methyltransferase for schizophrenia. Interestingly, of the two, only APOE has clear-cut and consistent evidence for a marginal association. Unraveling the underlying reasons is important in understanding both genetic etiology and architecture as well as how to use genetics to provide better personalized treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Adv Gerontol 2015 -1 28: 228-47 |
| PMID | 26856084 |
| Title | GENETICS OF HUMAN AGE RELATED DISORDERS. |
| Abstract | Aging is an inevitable biological phenomenon. The incidence of age related disorders (ARDs) such as cardiovascular diseases, cancer, arthritis, dementia, osteoporosis, diabetes, neurodegenerative diseases increase rapidly with aging. ARDs are becoming a key social and economic trouble for the world's elderly population (above 60 years), which is expected to reach 2 billion by 2050. Advancement in understanding of genetic associations, particularly through genome wide association studies (GWAS), has revealed a substantial contribution of genes to human aging and ARDs. In this review, we have focused on the recent understanding of the extent to which genetic predisposition may influence the aging process. Further analysis of the genetic association studies through pathway analysis several genes associated with multiple ARDs have been highlighted such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), cadherin 13 (CDH13), CDK5 regulatory subunit associated protein 1 (CDKAL-1), methylenetetrahydrofolate reductase (MTHFR), disrupted in schizophrenia 1 (DISC1), nitric oxide synthase 3 (NOS3), paraoxonase 1 (PON1), indicating that these genes could play a pivotal role in ARD causation. These genes were found to be significantly enriched in Jak-STAT signalling pathway, asthma and allograft rejection. Further, interleukin-6 (IL-6), insulin (INS), vascular endothelial growth factor A (VEGFA), estrogen receptor1 (ESR1), transforming growth factor, beta 1(TGFB1) and calmodulin 1 (CALM1) were found to be highly interconnected in network analysis. We believe that extensive research on the presence of common genetic variants among various ARDs may facilitate scientists to understand the biology behind ARDs causation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | Arch Med Sci 2015 Aug 11: 869-76 |
| PMID | 26322100 |
| Title | Apolipoprotein E polymorphism is associated with susceptibility to schizophrenia among Saudis. |
| Abstract | Apolipoprotein E (APOE) genotypes influence the phenotype of several neurodegenerative disorders including Alzheimer's and Parkinson disease and may affect schizophrenia pathogenesis. This study was undertaken to determine the association between APOE gene polymorphisms and schizophrenia in the Saudi population. APOE allele and genotype frequencies were studied in 380 Saudi subjects including schizophrenia patients and matched controls using polymerase chain reaction (PCR) and reverse-hybridization techniques. The frequencies of the APOE allele ?2 and genotypes ?2/?3 and ?2/?4 were significantly higher in the schizophrenia patients as compared to controls, suggesting that the ?2 allele and its heterozygous genotypes may increase the susceptibility to schizophrenia. In contrast, the frequencies of the ?3 allele and ?3/?3 genotype were lower in patients as compared to controls, suggesting a protective effect of APOE ?3 for schizophrenia. This study indicated that APOE ?4 was differentially associated with schizophrenia depending on the symptoms as the frequency of the ?4 allele was significantly higher in schizophrenia patients with positive symptoms. By contrast, no significant association between APOE ?4 and schizophrenia patients with negative symptoms was observed. Genotypes ?2/?2 and ?4/?4 were absent in patients and controls. Moreover, the age of onset was significantly lower in patients with the APOE ?2/?3 genotype. There was no significant difference in the frequencies of APOE alleles and genotypes between male and female schizophrenia patients. The results of this study clearly show that APOE alleles and genotypes are associated with risk of developing schizophrenia and early age of onset in Saudis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 69 | J Psychiatr Res 2015 Jan 60: 1-13 |
| PMID | 25287955 |
| Title | Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. |
| Abstract | Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 70 | PLoS ONE 2016 -1 11: e0153593 |
| PMID | 27078154 |
| Title | Development of a Melting Curve-Based Allele-Specific PCR of Apolipoprotein E (APOE) Genotyping Method for Genomic DNA, Guthrie Blood Spot, and Whole Blood. |
| Abstract | Genetic polymorphisms of apolipoprotein E (APOE) are associated with various health conditions and diseases, such as Alzheimer's disease, cardiovascular diseases, type 2 diabetes, etc. Hence, genotyping of APOE has broad applications in biomedical research and clinical settings, particularly in the era of precision medicine. The study aimed to develop a convenient and accurate method with flexible throughput to genotype the APOE polymorphisms. A melting curve-based allele-specific PCR method was developed to genotype two single nucleotide polymorphisms (SNPs) of APOE, i.e. rs429358 at codon 112 and rs7412 at codon 158. These two SNPs determine the genotype of APOE2, E3, and E4. PCR-based Sanger sequencing was used as the reference method for APOE genotyping. A 100% concordance rate was obtained in 300 subjects between the melting curve-based allele-specific PCR method and the Sanger sequencing method. This method was applied to a genetic association analysis of APOE and schizophrenia consisting of 711 patients with schizophrenia and 665 control subjects from Taiwan. However, no significant differences in the allele and genotype frequencies were detected between these two groups. Further experiments showed that DNA dissolved from blood collected on Guthrie filter paper and total blood cell lysate without DNA extraction can be used in the melting curve-based allele-specific PCR method. Thus, we suggest that this is a fast, accurate and robust APOE genotyping method with a flexible throughput and suitable for DNA template from different preparations. This convenient method shall meet the different needs of various research and clinical laboratories. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |