title: Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs.
abstract: Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.
authors.affiliation: Institute National de la Santé et de la Recherche Médicale (INSERM), U1043, Toulouse, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Adoue
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors.forename: Alicia
authors.initials: A
authors.lastname: Schiavi
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Light
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas Carlsson
authors.initials: JC
authors.lastname: Almlöf
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Lundmark
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.affiliation: Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
authors.forename: Shu-Huang
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Science, University of Leicester, Leicester, UK Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK Cardiogenics Consortium.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.affiliation: Cardiogenics Consortium INSERM UMRS 937 Pierre and Marie Curie University and Medical School, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Cambien
authors.affiliation: Cardiogenics Consortium Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Cardiogenics Consortium Department of Haematology, University of Cambridge, Cambridge, UK National Health Service Blood and Transplant, Cambridge Centre, Cambridge, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada tomi.pastinen@mcgill.ca.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
mesh_terms: D000483:Alleles; D044383:Black People / Q000235:genetics*; D002460:Cell Line; D002874:Chromosome Mapping / Q000379:methods*; D018983:DNA Footprinting; D005809:Genes, Regulator; D014644:Genetic Variation; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics; D044465:White People / Q000235:genetics*
chemical_list: D014157:Transcription Factors
keywords: NFκB; allelic expression; cis‐rSNPs; complex disease; repressor