1Int J Psychiatry Clin Pract 2001 -1 5: 71-3
PMID24937002
TitleClozapine-induced concordant agranulocytosis in monozygotic twins.
AbstractTwo monozygotic twin sisters were admitted to a psychiatric hospital and diagnosed as having first-episode schizophrenia. Clozapine treatment led to the complete remission of psychotic symptoms within a short time. In both twins the low leukocyte count was detected after 9 weeks of clozapine. Serological typing of the HLA system was performed and an identical pattern was detected in both twins: HLA-A: 28, 26; HLA-B: 49, 63; DR: 2 (vs 16), 12, 52; DQ:1. It is the first report of concordant manifestation of clozapine-induced agranulocytosis in monozygotic twins. Our case report of twins afflicted synchronously with schizophrenia and later with agranulocytosis after clozapine is of interest because it suggests that genetic factors may participate not only in timing of onset of schizophrenia, but also in the emergence and timing of agranulocytosis in response to clozapine treatment. ( Int J Psych Clin Pract 2001; 5:71-73).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
2Pharmacogenetics 2001 Mar 11: 135-41
PMID11266078
TitleFurther evidence of human leukocyte antigen-encoded susceptibility to clozapine-induced agranulocytosis independent of ancestry.
AbstractTo further examine the human leukocyte antigen (HLA)-encoded genetic susceptibility to clozapine-induced agranulocytosis (CA) we performed HLA-genotyping in a sample of German schizophrenic patients, who suffered from this haematotoxic side-effect. Thirty-one schizophrenic patients with CA (17 women and 14 men) and 77 schizophrenic comparison subjects (40 women and 37 men) were included in the study. HLA-genotyping included identification of major histocompatibility complex (MHC) class I (HLA-A, B, Cw) and class II (HLA-DR, DQ) antigens. CA was significantly associated with HLA-Cw*7 (P<0.02), DQB*0502 (P<0.04), DRB1*0101 (P<0.03) and DRB3*0202 (P<0.02). These HLA-haplotypes are also partly linked to other diseases with a strong genetic background. All other antigens revealed no association to this haematotoxic reaction. In addition, we did not find gender-related effects, whereas age seemed to be a further major risk factor of CA (P<0.0003). Thus, HLA loci may serve as genetic marker to identify subjects of different ethnic subgroups prone to this severe idiosyncratic drug reaction of clozapine. Further studies are needed to investigate whether these associations with CA are due to causal involvement or linkage disequilibrium.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
3Schizophr. Res. 2001 Jan 47: 1-12
PMID11163540
TitleSchizophrenia and HLA: a review.
AbstractA number of reports of genetic association of human leucocyte antigens (HLA) and alleles with schizophrenia have recently been published. A schizophrenia locus on chromosome 6p near the HLA region has also been reported, on the basis of linkage studies. We have therefore reviewed the investigations of association of HLA with schizophrenia published from 1974 to date, and have also briefly reviewed the chromosome 6p linkage studies. Two or more groups of investigators have reported association of each of the following HLA antigens or alleles with schizophrenia - A9 or its A24 subspecificity, A28, A10, DRB1*01 and DRw6. However, these results may represent Type I errors caused by small sample size, inappropriate diagnostic, laboratory and/or statistical methodology, and/or incorrectly chosen comparison subjects. Hypothesis-driven negative associations of DRB1*04 and DQB1*0602 with schizophrenia have also been reported. Taken together, however, HLA association investigations provide only weak evidence for the existence of either resistance or susceptibility loci for schizophrenia close to the HLA region at the 6p21.3 band and, indeed, recently reported investigations that controlled for most of these confounders found no evidence of association. Linkage studies suggest that a susceptibility locus may exist and that it may be within the HLA region, but again the evidence is far from conclusive. Further HLA association investigations should employ operational diagnostic criteria, comparison subjects screened for illness and HLA genotyping, and should include both association studies of candidate alleles and transmission disequilibrium and haplotype relative risk studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
4Neurosci. Lett. 2002 Aug 329: 201-4
PMID12165412
TitleHuman leukocyte antigen-A specificities and its relation with season of birth in Japanese patients with schizophrenia.
AbstractSeveral studies, including one from Japan, have observed an increase of Human Leukocyte Antigen (HLA)-A24 and A26 in schizophrenia, although others failed to observe the increase. No use of systematic diagnostic criteria and a not-adequately reliable typing technique might have affected the results in the previous studies. We investigated HLA-A specificities in Japanese patients with schizophrenia (DSM-IV), recruited from the same area as in the early Japanese study. A DNA-based technique (polymerase chain reaction-microtiter plate hybridization) was employed. No significant difference was observed in frequencies of any HLA-A specificities between patients and controls, including A24 and A26. No significant association was found between the HLA-A and birth-season in patients. Thus, no evidence was obtained for an association between HLA-A and schizophrenia from the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
5Am. J. Med. Genet. 2002 Apr 114: 315-20
PMID11920855
TitleInvestigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia.
AbstractThe hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
6Am. J. Med. Genet. 2002 Apr 114: 315-20
PMID11920855
TitleInvestigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia.
AbstractThe hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
7Am. J. Med. Genet. 2002 Jan 114: 42-5
PMID11840504
TitleHLA class I distribution in Japanese patients with schizophrenia.
AbstractSeveral Caucasian studies and one Japanese study have observed associations between human leukocyte antigen (HLA) class I specificities, including A24 (9) and A26 (10) and schizophrenia. Most of those studies were conducted in 1970s and early 1980s, when the typing technique of HLA was not adequately reliable. Also, an operational diagnostic system was not employed in many of the studies. The present study investigated frequencies of HLA-A specificities in schizophrenia patients (ICD-10 and DSM-III-R, n=98) and sex-matched healthy controls (n=392) from population in the southwestern part of Japan. HLA-B and -C specificities were studied in addition. Frequencies of subjects possessing A24 and A26 were not different between the patients and controls (54% and 24% in the patients and 62% and 24% in the controls, respectively). No significant difference was found in frequencies of other class I (A, B, and C) specificities between the patients and the controls. Thus, the present study provided no evidence for an association between the HLA class I specificities, including A24, A26, and others, and schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
8Am. J. Hum. Genet. 2006 Oct 79: 710-5
PMID16960807
TitleHLA-B maternal-fetal genotype matching increases risk of schizophrenia.
Abstractschizophrenia and human leukocyte antigen (HLA) matching between couples or between mothers and offspring have independently been associated with prenatal/obstetric complications, including preeclampsia and low birth weight. Here, we report the results of a family-based candidate-gene study that brings together these two disparate lines of research by assessing maternal-fetal genotype matching at HLA-A, -B, and -DRB1 as a risk factor of schizophrenia. We used a conditional-likelihood modeling approach with a sample of 274 families that had at least one offspring with schizophrenia or a related spectrum disorder. A statistically significant HLA-B maternal-fetal genotype-matching effect on schizophrenia was demonstrated for female offspring (P=.01; parameter estimate 1.7 [95% confidence interval 1.22-2.49]). Because the matching effect could be associated with pregnancy complications rather than with schizophrenia per se, these findings are consistent with the neurodevelopmental hypothesis of schizophrenia and with accumulating evidence that the prenatal period is involved in the origins of this disease. Our approach demonstrates how genetic markers can be used to characterize the biology of prenatal risk factors of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
9Can J Psychiatry 2006 May 51: 342-9
PMID16786814
TitleGenetic associations between delusional disorder and paranoid schizophrenia: A novel etiologic approach.
AbstractGenetic associations between delusional disorder and paranoid schizophrenia are not well understood, although involvement of biological factors has been suspected. We investigated the incidence of human leukocyte antigen (HLA) class I alleles in patients with delusional disorder and paranoid schizophrenia, first, to explore a possible immunogenetic etiology of these paranoid disorders and, second, to determine whether they share similar etiologic mechanisms.
We employed a nested case-control study design. Psychiatric reference data were available for 38,500 patients attending a hospital-based psychiatric outpatient department between 1998 and 2005. We enrolled 100 patients with delusional disorder and 50 patients with paranoid schizophrenia as the subject cases, using DSM-IV criteria. We considered equivalent numbers of healthy volunteers matched for age and ethnic background as control subjects. All subjects came from an India-born Bengali population. We applied the polymerase chain reaction-based molecular typing method to all patients and healthy subjects.
The HLA-A*03 gene is significantly associated with delusional disorder as well as with paranoid schizophrenia. This HLA gene alone or in linkage disequilibrium with other HLA genes or other closely linked non-HLA genes may influence susceptibility to delusional disorder and paranoid schizophrenia.
The study reveals important associations between HLA genes and paranoid disorders. Delusional disorder and paranoid schizophrenia may share similar etiologic mechanisms. This preliminary observation may help our understanding of the genetic basis of these paranoid disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
10Mol. Psychiatry 2007 Mar 12: 264-72
PMID17102800
TitleAssociations between Chlamydophila infections, schizophrenia and risk of HLA-A10.
AbstractSeveral microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. Our aim here was to analyze frequencies of three types of Chlamydiaceae in schizophrenic patients (n=72), random controls (n=225) and hospital-patient controls (n=36), together with HLA-A genotypes. Patients were diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-IV. Blood samples were collected at the beginning of hospitalization and analyzed with Chlamydiaceae species-specific polymerase chain reaction (PCR). Control panels consisted of randomly selected volunteers and hospitalized, non-schizophrenic patients. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 x 10(-10), odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 x 10(-7), OR=24.39). schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 x 10(-5), OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
11Mol. Psychiatry 2007 Mar 12: 264-72
PMID17102800
TitleAssociations between Chlamydophila infections, schizophrenia and risk of HLA-A10.
AbstractSeveral microbes have been suspected as pathogenetic factors in schizophrenia. We have previously observed increased frequencies of chlamydial infections and of human lymphocyte antigen (HLA)-A10 in independent studies of schizophrenia. Our aim here was to analyze frequencies of three types of Chlamydiaceae in schizophrenic patients (n=72), random controls (n=225) and hospital-patient controls (n=36), together with HLA-A genotypes. Patients were diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders-IV. Blood samples were collected at the beginning of hospitalization and analyzed with Chlamydiaceae species-specific polymerase chain reaction (PCR). Control panels consisted of randomly selected volunteers and hospitalized, non-schizophrenic patients. We found chlamydial infection in 40.3% of the schizophrenic patients compared to 6.7% in the controls. The association of schizophrenia with Chlamydiaceae infections was highly significant (P=1.39 x 10(-10), odds ratio (OR)=9.43), especially with Chlamydophila psittaci (P=2.81 x 10(-7), OR=24.39). schizophrenic carriers of the HLA-A10 genotype were clearly most often infected with Chlamydophila, especially C. psittaci (P=8.03 x 10(-5), OR=50.00). Chlamydophila infections represent the highest risk factor yet found to be associated with schizophrenia. This risk is even further enhanced in carriers of the HLA-A10 genotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
12Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Dec 32: 1834-7
PMID18786593
TitleAssociation study of HLA-A gene and schizophrenia in Han Chinese from Taiwan.
AbstractDysregulation of the immune response has been proposed as a precipitating factor of schizophrenia, and human leukocyte antigens (HLA) play a critical role in regulating the cascade of immunological reaction. Hence, many studies have investigated the relationship between the HLA system and schizophrenia. HLA is a complex gene family that contains several highly polymorphic genes, while the HLA-A gene is the most often studied gene to be associated with schizophrenia in the literature. A recent study reported that the interaction of the HLA-A10 allele and Chlamydial infection was highly associated with schizophrenia in a German population, which prompted us to investigate whether the HLA-A gene was also associated with schizophrenia in our population. Using a sequencing-based HLA typing method, we determined the HLA-A genotypes in 377 Han Chinese patients with schizophrenia (214 males, 163 females) and 321 non-psychotic Han Chinese control subjects (164 males, 157 females) from Taiwan. In total, 26 DNA-defined HLA-A alleles were identified in this sample. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of schizophrenia in this sample. As different populations have different HLA polymorphisms, an examination of the relationship of other HLA genes and schizophrenia in our population, with a larger sample size, is warranted in the future.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
13Indian J Psychiatry 2008 Jul 50: 166-70
PMID19742184
TitleAnalysis of the role of human leukocyte antigen class-I genes to understand the etiopathology of schizophrenia.
Abstractschizophrenia is the paradigmatic illness of psychiatry. The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort.
In this study, we investigated the incidence of human leukocyte antigen (HLA) Class I antigens to understand the role of HLA genes in schizophrenia.
India born schizophrenic patients in and around Siliguri who attended outpatient department (OPD) of Department of Psychiatry, North Bengal Medical College and Hospital were considered for the present study. After the longitudinal follow up, 50 patients were enrolled for the study. The same number of age, sex and ethnically matched healthy subjects were considered as control. Low resolution polymerase chain reaction-sequence specific primer method was applied for typing the HLA antigens.
The phenotype frequencies were calculated by direct count. chi(2) test was done to compare the frequency of each antigen among the patients and control group and it was followed by Fisher's exact test. Relative risk was estimated by using Haldane's method.
The result showed that some of the HLA antigens are associated with the schizophrenia and significant increase were observed for HLA A*03 antigen along with the significant decrease for HLA A*25, A*31 and HLA B*51.
The study provides the evidence for the possible existence of susceptibility locus for schizophrenia within the HLA region. This preliminary observation may help to understand the etiological basis of this disorder and the study may further strengthen the HLA antigens as the marker for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
14Indian J Psychiatry 2008 Jul 50: 166-70
PMID19742184
TitleAnalysis of the role of human leukocyte antigen class-I genes to understand the etiopathology of schizophrenia.
Abstractschizophrenia is the paradigmatic illness of psychiatry. The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort.
In this study, we investigated the incidence of human leukocyte antigen (HLA) Class I antigens to understand the role of HLA genes in schizophrenia.
India born schizophrenic patients in and around Siliguri who attended outpatient department (OPD) of Department of Psychiatry, North Bengal Medical College and Hospital were considered for the present study. After the longitudinal follow up, 50 patients were enrolled for the study. The same number of age, sex and ethnically matched healthy subjects were considered as control. Low resolution polymerase chain reaction-sequence specific primer method was applied for typing the HLA antigens.
The phenotype frequencies were calculated by direct count. chi(2) test was done to compare the frequency of each antigen among the patients and control group and it was followed by Fisher's exact test. Relative risk was estimated by using Haldane's method.
The result showed that some of the HLA antigens are associated with the schizophrenia and significant increase were observed for HLA A*03 antigen along with the significant decrease for HLA A*25, A*31 and HLA B*51.
The study provides the evidence for the possible existence of susceptibility locus for schizophrenia within the HLA region. This preliminary observation may help to understand the etiological basis of this disorder and the study may further strengthen the HLA antigens as the marker for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
15Asian J Psychiatr 2011 Dec 4: 277-83
PMID23051162
TitleImmunomodulation in schizophrenia: A study among the Indian schizophrenia patients of Siliguri, West Bengal.
AbstractAuthors investigated the circumstantial evidence for autoimmunity in schizophrenia patients of Siliguri by considering the immune parameters like HLA Class I genes, IL-2 and IL6 and T cell subsets. Low resolution PCR-SSP method was applied for typing the HLA genes. Serum levels of IL-2 and IL-6 were measured by ELISA method. The CD4+ and CD8+ subset count were done using flow cytometry. A significant increase in HLA A*03 gene was observed in patients along with the significant decrease of HLA-A*31 and HLA-B*51. Both IL-2 and IL-6 were found to have decreased levels in the patients. Although the mean percentage of CD4+ and CD8+ cells was higher in patients but not significantly higher than controls. These cumulative preliminary findings are suggestive of alterations in the immune system of schizophrenia patients of this region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
16Psychiatry Res 2011 Sep 189: 215-9
PMID21459456
TitleStudy of HLA Class I gene in Indian schizophrenic patients of Siliguri, West Bengal.
AbstractThe authors studied the prevalence of the human leukocyte antigen (HLA) Class I gene in 136 (85 male, 51 female) India-born schizophrenia patients residing in and around the Siliguri subdivision of West Bengal by the PCR-SSP method. The control group consisted of 150 age- and sex-matched healthy individuals from the same ethnic group as the patients. Increased frequency of HLA A*03 as well as decreased frequencies of HLA A*31 and HLA B*51, was noted. The study suggests the possible existence of a susceptibility locus for schizophrenia within the HLA region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
17Psychiatry Res 2011 Sep 189: 215-9
PMID21459456
TitleStudy of HLA Class I gene in Indian schizophrenic patients of Siliguri, West Bengal.
AbstractThe authors studied the prevalence of the human leukocyte antigen (HLA) Class I gene in 136 (85 male, 51 female) India-born schizophrenia patients residing in and around the Siliguri subdivision of West Bengal by the PCR-SSP method. The control group consisted of 150 age- and sex-matched healthy individuals from the same ethnic group as the patients. Increased frequency of HLA A*03 as well as decreased frequencies of HLA A*31 and HLA B*51, was noted. The study suggests the possible existence of a susceptibility locus for schizophrenia within the HLA region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
18Brain Behav. Immun. 2013 Aug 32: 51-62
PMID23395714
TitleExpression of immune genes on chromosome 6p21.3-22.1 in schizophrenia.
Abstractschizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ?2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
19Brain Behav. Immun. 2013 Aug 32: 51-62
PMID23395714
TitleExpression of immune genes on chromosome 6p21.3-22.1 in schizophrenia.
Abstractschizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. ?2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
20Immunobiology 2013 May 218: 738-44
PMID23083632
TitleParadoxical downregulation of HLA-A expression by IFN? associated with schizophrenia and noncoding genes.
AbstractNeuronal MHC/HLA regulates the synapses of the central nervous system (CNS). The expression of MHC/HLA is, in turn, regulated by immune cytokines. We were therefore interested in the regulation of schizophrenia-associated HLA antigens, specifically their regulation of expression by interferons. We had previously observed a moderately increased frequency of HLA-A10 expression in schizophrenic patients. While searching for the "true" disease gene near the HLA-A gene, we discovered that homozygosity of the HLA-J M80469 pseudogene allele, in combination with HLA-A10 or HLA-A9, was associated with a high risk of schizophrenia (HLA-A10 relative risk = 29.33, p = 0.00019, patients N = 77, controls N = 214). The allele HLA-J M80468, which codes for interferon-inducible mRNA, conferred protection on carriers of HLA-A9 and HLA-A10 (HLA-A10 relative risk = 0.022, p = 0.00017). Functional analysis revealed that interferon ? (IFN?) downregulated the expression of HLA-A9 and HLA-A10 in monocytes from HLA-J M80469 homozygous patients but not from carriers of the HLA-J M80468 allele. This is the first demonstration of an inverse effect of IFN? on HLA expression that is associated with non-coding gene variants and schizophrenia. Our findings suggest that the interferons secreted during acute and chronic infections may interfere in synaptic regulation via neuronal HLA and that this disturbance in synaptic regulation may induce the symptoms of mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
21Immunobiology 2013 May 218: 738-44
PMID23083632
TitleParadoxical downregulation of HLA-A expression by IFN? associated with schizophrenia and noncoding genes.
AbstractNeuronal MHC/HLA regulates the synapses of the central nervous system (CNS). The expression of MHC/HLA is, in turn, regulated by immune cytokines. We were therefore interested in the regulation of schizophrenia-associated HLA antigens, specifically their regulation of expression by interferons. We had previously observed a moderately increased frequency of HLA-A10 expression in schizophrenic patients. While searching for the "true" disease gene near the HLA-A gene, we discovered that homozygosity of the HLA-J M80469 pseudogene allele, in combination with HLA-A10 or HLA-A9, was associated with a high risk of schizophrenia (HLA-A10 relative risk = 29.33, p = 0.00019, patients N = 77, controls N = 214). The allele HLA-J M80468, which codes for interferon-inducible mRNA, conferred protection on carriers of HLA-A9 and HLA-A10 (HLA-A10 relative risk = 0.022, p = 0.00017). Functional analysis revealed that interferon ? (IFN?) downregulated the expression of HLA-A9 and HLA-A10 in monocytes from HLA-J M80469 homozygous patients but not from carriers of the HLA-J M80468 allele. This is the first demonstration of an inverse effect of IFN? on HLA expression that is associated with non-coding gene variants and schizophrenia. Our findings suggest that the interferons secreted during acute and chronic infections may interfere in synaptic regulation via neuronal HLA and that this disturbance in synaptic regulation may induce the symptoms of mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
22Hum. Mol. Genet. 2014 Nov 23: 6088-95
PMID24943592
TitleExcess of homozygosity in the major histocompatibility complex in schizophrenia.
AbstractGenome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
23PLoS ONE 2015 -1 10: e0144719
PMID26674772
TitleEvidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.
AbstractMultiple risk variants of schizophrenia have been identified by Genome-wide association studies (GWAS). As a complement for GWAS, previous pathway-based analysis has indicated that cell adhesion molecules (CAMs) pathway might be involved in the pathogenesis of schizophrenia. However, less replication studies have been reported. Our objective was to investigate the association between CAMs pathway and schizophrenia in the Chinese Han population. We first performed a pathway analysis utilizing our previous GWAS data. The CAMs pathway (hsa04514) was significantly associated with schizophrenia using hybrid gene set-based test (P = 1.0310-10) and hypergeometric test (P = 5.0410-6). Moreover, 12 genes (HLA-A, HLA-C, HLA-DOB, HLA-DPB1, HLA-DQA2, HLA-DRB1, MPZ, CD276, NLGN1, NRCAM, CLDN1 and ICAM3) were modestly significantly associated with schizophrenia (P<0.01). Then, we selected one promising gene neuroligin 1 (NLGN1) to further investigate the association between eight significant SNPs and schizophrenia in an independent sample (1814 schizophrenia cases and 1487 healthy controls). Our study showed that seven SNPs of NLGN1 and two haplotype blocks were significantly associated with schizophrenia. This association was confirmed by the results of combined analysis. Among them, SNP rs9835385 had the most significant association with schizophrenia (P = 2.8310-7). Furthermore, in silico analysis we demonstrated that NLGN1 is preferentially expressed in human brain and SNP rs1488547 was related to the expression level. We validated the association of CAMs pathway with schizophrenia in pathway-level and identified one susceptibility gene NLGN1. Further investigation of the roles of CAMs pathway in the pathogenesis of schizophrenia is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
24Transl Psychiatry 2015 -1 5: e608
PMID26218850
TitleA double amino-acid change in the HLA-A peptide-binding groove is associated with response to psychotropic treatment in patients with schizophrenia.
AbstractThe choice of an efficient psychotropic treatment for patients with schizophrenia is a key issue to improve prognosis and quality of life and to decrease the related burden and costs. As for other complex disorders, response to drugs in schizophrenia is highly heterogeneous and the underlying molecular mechanisms of this diversity are still poorly understood. In a carefully followed-up cohort of schizophrenic patients prospectively treated with risperidone or olanzapine, we used a specially designed single-nucleotide polymorphism (SNP) array to perform a large-scale genomic analysis and identify genetic variants associated with response to psychotropic drugs. We found significant associations between response to treatment defined by the reduction in psychotic symptomatology 42 days after the beginning of treatment and SNPs located in the chromosome 6, which houses the human leukocyte antigen (HLA). After imputation of the conventional HLA class I and class II alleles, as well as the amino-acid variants, we observed a striking association between a better response to treatment and a double amino-acid variant at positions 62 and 66 of the peptide-binding groove of the HLA-A molecule. These results support the current notion that schizophrenia may have immune-inflammatory underpinnings and may contribute to pave the way for personalized treatments in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
25Transl Psychiatry 2015 -1 5: e608
PMID26218850
TitleA double amino-acid change in the HLA-A peptide-binding groove is associated with response to psychotropic treatment in patients with schizophrenia.
AbstractThe choice of an efficient psychotropic treatment for patients with schizophrenia is a key issue to improve prognosis and quality of life and to decrease the related burden and costs. As for other complex disorders, response to drugs in schizophrenia is highly heterogeneous and the underlying molecular mechanisms of this diversity are still poorly understood. In a carefully followed-up cohort of schizophrenic patients prospectively treated with risperidone or olanzapine, we used a specially designed single-nucleotide polymorphism (SNP) array to perform a large-scale genomic analysis and identify genetic variants associated with response to psychotropic drugs. We found significant associations between response to treatment defined by the reduction in psychotic symptomatology 42 days after the beginning of treatment and SNPs located in the chromosome 6, which houses the human leukocyte antigen (HLA). After imputation of the conventional HLA class I and class II alleles, as well as the amino-acid variants, we observed a striking association between a better response to treatment and a double amino-acid variant at positions 62 and 66 of the peptide-binding groove of the HLA-A molecule. These results support the current notion that schizophrenia may have immune-inflammatory underpinnings and may contribute to pave the way for personalized treatments in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
26Brain Behav. Immun. 2015 May 46: 311-8
PMID25728236
TitleA schizophrenia-associated HLA locus affects thalamus volume and asymmetry.
AbstractGenes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analysed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics