Common regulatory variation impacts gene expression in a cell type dependent manner

By A. Dimas, S. Deutsch, Barbara E. Stranger, Stephen B. Montgomery, C. Borel, Homa Attar-Cohen, Catherine E. Ingle, C. Beazley, Maria Gutierrez Arcelus, Magdalena Sekowska and 5 more. Science, 2009

829 citations recorded by the source corpus.

Tissue-Specific Control The effect of genetic variation on gene expression and phenotype among individuals is largely unknown. Dimas et al. (p. 1246, published online 30 July 2009) show that in humans there are several genes whose allelic expression varies in a tissue-specific manner and are apparently controlled by cis elements. Up to 80% of variants seem to have tissue-specific functions when compared in fibroblasts, as well as B cells and T cells. This variation among regulatory variants correlated with transcript complexity, which suggests that some of the observed regulatory variation is due to genotype-specific use of transcripts and transcription start sites. Genetic variation in regulatory elements among humans affects gene expression in a tissue-specific manner. Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (single-nucleotide polymorphisms) on three cell types of 75 individuals. We detected cell type–specific genetic effects, with 69 to 80% of regulatory variants operating in a cell type–specific manner, and identified multiple expressive quantitative trait loci (eQTLs) per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type–specific eQTLs were found at larger distances from genes and at lower effect size, similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell-type specificity.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0d5d35d9992a30ac5db6e75b7cace703868938e3

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Citations in the corpus

The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies (2017, neutral): “The polymorphism data present in HGMD should be viewed with a degree of caution owing to (i) the possibility that an observed disease association may be simply due to a linkage disequilibrium effect and (ii) the fact that in vitro studies are not invariably accurate indicators of in vivo functionali”
Annotation of functional variation in personal genomes using RegulomeDB (2012, methodology): “We also include a large collection of eQTL (Myers et al. 2007; Stranger et al. 2007; Schadt et al. 2008; Veyrieras et al. 2008; Dimas et al. 2009; Gibbs et al. 2010; Montgomery et al. 2010; Pickrell et al. 2010; Zeller et al. 2010), dsQTL (Degner et al. 2012), and ChIP-exo (Rhee and Pugh 2011) data.”
RNA Sequencing and Analysis (2015, positive): “For instance, several studies have performed eQTL analysis across multiple tissues, indicating that genetic regulatory elements can have tissue-specific effects (Petretto et al. 2006; Schadt et al. 2008; Dimas et al. 2009; Kwan et al. 2009; Grundberg et al. 2012; Flutre et al. 2013).”
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis (2010, background): “Recent evidence that tissue-specific eQTL signals are preferentially located in regulatory sequences some distance from transcriptional start sites 63 —in common with many complex trait association signals—suggests that further dissection of these regions should improve understanding of the genomic…”
Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations (2010, methodology): “To perform a control experiment where the trait is gene expression, we used cis eQTLs (10(23) P-value permutation threshold) detected in LCLs derived from 75 unrelated individuals of Western European origin from the GenCord project [19].”
Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility (2010, background): “-regulated eQTLs in monocytes. Even if cell-specific eQTLs exist”