title: Global analysis of the impact of environmental perturbation on cis-regulation of gene expression.
abstract: Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24 h), and PGE₂ (t = 24 h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (n(total) = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene ± 250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX-specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (∼1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here.
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada. eg5@sanger.ac.uk
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Veronique
authors.initials: V
authors.lastname: Adoue
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.forename: Qing Ling
authors.initials: QL
authors.lastname: Duan
authors.forename: Kevin C L
authors.initials: KC
authors.lastname: Lam
authors.forename: Vonda
authors.initials: V
authors.lastname: Koka
authors.forename: Andreas
authors.initials: A
authors.lastname: Kindmark
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Kelan
authors.initials: K
authors.lastname: Tantisira
authors.forename: Hans
authors.initials: H
authors.lastname: Mallmin
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Olle
authors.initials: O
authors.lastname: Nilsson
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004781:Environmental Exposure; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D009928:Organ Specificity / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects / Q000235:genetics*
chemical_list: D055396:Bone Morphogenetic Protein 2; D005819:Genetic Markers; D003907:Dexamethasone; D015232:Dinoprostone