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Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33321 | GEO | 2011/10/29

SECONDARY ACCESSION(S): PRJNA149295

REPOSITORIES: GEO

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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.

Project description:DNA from Epstein-Barr virus (EBV)-transformed lymphocyte cell lines (LCLs) has proven very useful for studies of genetic sequence polymorphisms. Whether EBV-LCL DNA is suitable for methylation studies is less clear. We conduct a genome-wide methylation investigation using an array set with 45 million probes to investigate the methylome of EBV-LCL DNA and technical duplicates of whole blood (WB) DNA from the same 10 individuals. Methylation sites that show variation between individuals are potentially useful as biomarkers in disease studies. Our comparison is, therefore, focused specifically on these methylation variable sites. The sample correlations (i.e., a measure of whether the rank of the signals remains consistent between two samples from the same individual) for the methylation variable probes ranged from 0.69-0.78 for the WB duplicates and from 0.27-0.72 for WB versus EBV-LCL. To compare the pattern of the methylation signals, we grouped adjacent probes based on their inter-correlations. These analyses showed ~29,000 blocks in WB and ~14,000 blocks in EBV-LCL. Furthermore, merely 31% of the methylated regions detected in WB were detectable in EBV-LCLs. Our study shows that there are substantial differences in the DNA methylation patterns between EBV-LCL and WB. Thus, EBV-LCL DNA cannot be used as a proxy for WB DNA in methylation studies. The methylation of technical duplicates of DNA extracted from whole blood from 10 individuals, as well as DNA extracted from EBV-transformed lymphocyte cell lines (EBV-LCL) from the same samples of whole blood, are investigated using the Affymetrix GeneChip Human Tiling 2.0R array set. In total, 30 samples from 10 individuals were investigated on 7 arrays. The supplementary "GSE35204_ChrXX_bgc_qt.txt" files contain the background-corrected and quantile-normalized data for all 30 samples per chromosome. The files include 32 columns: 'Seq' refers to the chromosome, 'Pos' indicates the position in the genome on that chromosome, and columns 3-32 indicate the sample numbers.

Project description:Renewable in vitro cell cultures, such as lymphoblastoid cell lines (LCLs), have facilitated studies that contributed to our understanding of genetic influence on human traits. However, the degree to which cell lines faithfully maintain differences in donor-specific phenotypes is still debated. We have previously reported that standard cell line maintenance practice results in a loss of donor-specific gene expression signatures in LCLs. An alternative to the LCL model is the induced pluripotent stem cell (iPSC) system, which carries the potential to model tissue-specific physiology through the use of differentiation protocols. Still, existing LCL banks represent an important source of starting material for iPSC generation, and it is possible that the disruptions in gene regulation associated with long-term LCL maintenance could persist through the reprogramming process. To address this concern, we studied the effect of reprogramming mature LCLs to iPSCs on the ensuing gene expression patterns within and between six unrelated donor individuals. We show that the reprogramming process results in a recovery of donor-specific gene regulatory signatures. Since environmental contributions are unlikely to be a source of individual variation in our system of highly passaged cultured cell lines, our observations suggest that the effect of genotype on gene regulation is more pronounced in the iPSCs than in the LCL precursors. Our observations indicate that iPSCs can be a powerful model system for studies of phenotypic variation across individuals in general, and the genetic association with variation in gene regulation in particular. We further conclude that LCLs are an appropriate starting material for iPSC generation. Whole genome gene expression data was collected for 34 samples including 17 iPSC lines and 17 LCL lines on the Illumina HT-12 v4 Expression BeadChip array platform. Three biological replicates of each individual were included in the study, except for one individual for which only two replicates were obtained.

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Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent

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