Expression of immune genes on chromosome 6p21.3–22.1 in schizophrenia

Abstract

Schizophrenia 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. β2 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.

A schizophrenia-associated HLA locus affects thalamus volume and asymmetry

“…Furthermore, both HLA-A and ZNRD1 contain SNPs associated with schizophrenia by GWAS; rs2524005 is intronic in HLA-A (Bergen et al, 2012) and rs8321 is in the 3 0 untranslated region of ZNRD1 (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013b). In addition, HLA-A expression has shown evidence for alteration in schizophrenic patients (Sinkus et al, 2013). The most significantly associated SNP outside the HLA locus, in another recent GWAS study, is linked to a locus affecting HLA-A mRNA level in brain (Schizophrenia Working Group of the Psychiatric Genomics, 2014).…”

“…HLA class I proteins present peptides to cytotoxic T-cells (CD8+), while HLA class II proteins present peptides to helper T-cells (CD4+) participating in the production of antibodies by B-cells (Shiina et al, 2009;Trowsdale and Knight, 2013). The expression of cytokines and genes of the HLA region, critical components of the immune response, may be altered in peripheral immune cells and in glial cells of schizophrenic patients (Bernstein et al, 2015;Goudriaan et al, 2014;Miller et al, 2011;Sinkus et al, 2013). Several studies have shown a co-segregation of autoimmune diseases, chronic inflammation and maternal infection with schizophrenia (Bergink et al, 2014;Bernstein et al, 2015;Horvath and Mirnics, 2014;Knuesel et al, 2014;Stringer et al, 2014).…”

Applications of blood-based protein biomarker strategies in the study of psychiatric disorders

“…Similarly polymorphisms of the IL1B gene have been linked to decreased prefrontal metabolic rates as determined using PET imaging (Papiol et al, 2007). Genome-wide association studies (GWAS) have also implicated tissue growth factor beta (TGF-beta) and tumour necrosis factor receptor 1 (TNFR1) signalling changes (Jia et al, 2010) and the major histocompatability complex (MHC) (Purcell et al, 2009;Stefansson et al, 2009) region on chromosome 6p21.3 to 6p22.1 in schizophrenia and post-mortem transcriptomic studies have shown that brains from schizophrenia patients have significant alterations in mRNA transcripts arising from genes in the MHC region (Kano and Altered, 2011;Sinkus et al, 2013). Considering this evidence, it is interesting to note that activation of the peripheral immune system over a prolonged duration causes activation of the brain's immune system and this has been linked to the onset of depressive episodes (Dantzer et al, 2008).…”

Major Histocompatibility Complex I in Brain Development and Schizophrenia

“…That assumption was disproved about 15 years ago when the Shatz laboratory made the surprising discovery that MHCI molecules are expressed in the CNS throughout development (41). mRNA encoding MHCI is expressed in neurons and glia from multiple brain regions in many species including mice, rats, cats, marmosets, and humans (19–21, 41–45). MHCI protein levels in the rodent cerebral cortex are highest during neonatal development and decrease to lower levels late in development and into adulthood (45, 46), followed by an increase again with aging, at least in glial cells (47).…”

“…Inflammation in the CNS is present in postmortem brains and cytokine levels are altered in the blood, brain, and cerebrospinal fluid (CSF) in SZ (4, 16, 17); specific cytokines may be correlated with periods of active psychosis (18). The expression of many immune-related genes in the brain, including MHC genes, is also altered in SZ (Horvath and Mirnics review, this issue) (19–21). Reports showing a relationship between SZ endophenotypes and MHC class I (MHCI) expression support this association (8).…”