1Schizophr Bull 2009 Nov 35: 1163-82
PMID18552348
TitleSchizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.
AbstractMany 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 Keywordsschizophrenia, schizophrenic
2Schizophr. Res. 2015 Dec 169: 1-9
PMID26481614
TitleAssociation study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population.
Abstractschizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed.
SCZ Keywordsschizophrenia, schizophrenic
3Brain Behav. Immun. 2016 Mar -1: -1
PMID26971470
TitleContribution of IL-10 and its -592 A/C polymorphism to cognitive functions in first-episode drug-naive schizophrenia.
AbstractNumerous studies have shown that proinflammatory cytokines produced by immune cells in the brain have deleterious effects on cognitive functions. In contrast, IL-10, an anti-inflammatory cytokine, can be neuroprotective and prevent neuronal dysfunction. However, few studies have linked the role of IL-10 to cognitive deficits in schizophrenia. In this study, serum IL-10 levels and genotypes for the IL10 -592 A/C promoter polymorphism were measured in a cohort of first-episode drug-na´ve schizophrenic patients (FEDN-S) (n=256) and healthy control subjects (HC) (n=540). All participants were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). In a separate transcriptomic data set containing 577 healthy human brain samples, we analyzed IL-10 and IL-10 RA/B-associated genetic networks in order to ascertain potential functions for IL-10 in the brain. We found a significant difference in allelic frequency between FEDN-S and HC subjects. The A allelic variant was associated with reduced serum IL-10 levels and worse attentional performance in FEDN-S but not in HC subjects. Moreover, serum IL-10 levels were correlated with the extent of cognitive impairment, especially attentional performance in the schizophrenic A-allele carriers. In human brain transcriptomic coexpression analysis, we found that genes most significantly co-expressed with IL10 were associated with synaptic vesicle transportation, and both IL10RA and IL10RB were most significantly co-expressed not only with genes that regulate inflammation but also with those that participate in synaptic formation. The IL10-592 A/C genetic variant was more common in schizophrenic patients than HC and was associated with lower IL-10 serum levels and worse attentional performance in these patients. Furthermore, the IL10 gene and its receptors in the healthy human brain appear to regulate inflammation and synaptic functions that are important for cognition, and hence its deficiency in schizophrenia may contribute to cognitive impairment.
SCZ Keywordsschizophrenia, schizophrenic
4Brain Behav. Immun. 2016 Mar -1: -1
PMID26971470
TitleContribution of IL-10 and its -592 A/C polymorphism to cognitive functions in first-episode drug-naive schizophrenia.
AbstractNumerous studies have shown that proinflammatory cytokines produced by immune cells in the brain have deleterious effects on cognitive functions. In contrast, IL-10, an anti-inflammatory cytokine, can be neuroprotective and prevent neuronal dysfunction. However, few studies have linked the role of IL-10 to cognitive deficits in schizophrenia. In this study, serum IL-10 levels and genotypes for the IL10 -592 A/C promoter polymorphism were measured in a cohort of first-episode drug-na´ve schizophrenic patients (FEDN-S) (n=256) and healthy control subjects (HC) (n=540). All participants were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). In a separate transcriptomic data set containing 577 healthy human brain samples, we analyzed IL-10 and IL-10 RA/B-associated genetic networks in order to ascertain potential functions for IL-10 in the brain. We found a significant difference in allelic frequency between FEDN-S and HC subjects. The A allelic variant was associated with reduced serum IL-10 levels and worse attentional performance in FEDN-S but not in HC subjects. Moreover, serum IL-10 levels were correlated with the extent of cognitive impairment, especially attentional performance in the schizophrenic A-allele carriers. In human brain transcriptomic coexpression analysis, we found that genes most significantly co-expressed with IL10 were associated with synaptic vesicle transportation, and both IL10RA and IL10RB were most significantly co-expressed not only with genes that regulate inflammation but also with those that participate in synaptic formation. The IL10-592 A/C genetic variant was more common in schizophrenic patients than HC and was associated with lower IL-10 serum levels and worse attentional performance in these patients. Furthermore, the IL10 gene and its receptors in the healthy human brain appear to regulate inflammation and synaptic functions that are important for cognition, and hence its deficiency in schizophrenia may contribute to cognitive impairment.
SCZ Keywordsschizophrenia, schizophrenic