Unknown,Transcriptomics,Genomics,Proteomics

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Comparative Genome-wide expression profiling of ADLD whole blood and fibroblasts cell lines.

ABSTRACT: Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by autonomic dysfunction, followed by cerebellar and pyramidal features. ADLD is caused by duplication of the lamin B1 gene (LMNB1), which leads to its increased expression. The molecular pathways involved in the disease are still poorly understood. Hence, we analyzed global gene expression in fibroblasts and whole blood of LMNB1 duplication carriers and used Gene Set Enrichment Analysis (GSEA) to explore their gene signatures. We found that LMNB1 duplication is associated with dysregulation of genes involved in the immune system, neuronal and skeletal development. Genes with an altered transcriptional profile clustered in specific genomic regions. To identify altered pathways in ADLD, we performed a whole genome expression profiling on fibroblasts cell lines derived from 4 ADLD, 3 controls siblings, 2 age match controls, 2 uninvestigated samples; and from 4 ADLD whole blood, 8 controls siblings and 1 uninvestigated sample.

ORGANISM(S): Homo sapiens

SUBMITTER: Sabina Capellari

PROVIDER: E-GEOD-65368 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The degree to which the level of genetic variation for gene expression is shared across multiple tissues has important implications for research investigating the role of expression on the aetiology of complex human traits and diseases. In the last few years, a number of studies have been published reporting the extent of overlap in expression quantitative trait loci (eQTL) identified in multiple tissues or cell types. Whilst these studies provide important information on the regulatory control of genes across tissues, their limited power means they can typically only explain a small proportion of genetic variation for gene expression. Here, using expression data from monozygotic twins (MZ), we investigate the genetic control of gene expression in lymphoblastoid cell lines (LCL) and whole blood (WB). We estimate the genetic correlation which represents the combined effects of all causal loci across the whole genome and is a measure of the level of common genetic control of gene expression between the two RNA sources. Our results show that, when averaged across the genome, mean levels of genetic correlation for gene expression in LCL and WB samples are close to zero. We support our results with evidence from gene expression in an independent sample of LCL, T-cells and Fibroblasts. In addition, we provide evidence that housekeeping genes, which maintain basic cellular functions, are more likely to have high genetic correlations between the RNA sources than non-housekeeping gene, implying a relationship between the transcript function and the degree to which a gene has tissue specific genetic regulatory control. In this study, the global genetic control of expression levels for 9555 genes were examined from two samples of RNA sources, collected on pairs of monozygotic (MZ) twins. From each individual, gene expression profiles were generated whole blood (WB), collected using the PAXgeneTM tube system, and lymphoblastoid cell lines (LCL). Using expression data collected from MZ twins is a powerful means of estimating the genetic contribution of expression variation. In particular, the observed phenotypic covariance in gene expression in LCLs and WBs between MZ twins can be partitioned into variation due to within-person environmental effects and between-person genetic effects.

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Comparative Genome-wide expression profiling of ADLD whole blood and fibroblasts cell lines.

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