Unknown,Transcriptomics,Genomics,Proteomics

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Affymetrix Human Exon 1.0 ST array analysis of lymphoblastoid cell lines

ABSTRACT: This experiment accompanies the main analysis using a custom MHC array to define the first high-resolution, strand-specific transcriptional map of the MHC, defining differences in gene expression for three common haplotypes associated with autoimmune disease. Unstimulated samples for each haplotype were hybridised to Affymetrix Human Exon 1.0 ST arrays as well the custom MHC array. Exon array data were used to assess the concordance of signal obtained from the two platforms and to investigate the extent of alternative splicing in the MHC, and how it compares to the rest of the genome. Lymphoblastoid cell lines carrying three common autoimmunity haplotypes (COX, PGF, QBL) were analysed in triplicate using the Affymetrix Human Exon 1.0 ST Array.

ORGANISM(S): Homo sapiens

SUBMITTER: Claire Vandiedonck

PROVIDER: E-GEOD-22454 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Genome wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by an exon microarray study. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders. There were 20 anterior cingulate postmortem brain samples that were extracted for total RNA, and analyzed using Affymetrix Exon Array (bipolar disorder subjects n = 9, controls n = 11).

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Affymetrix Human Exon 1.0 ST array analysis of lymphoblastoid cell lines

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