Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs
2014 (English)In: Molecular Systems Biology, ISSN 1744-4292, Vol. 10, no 10, 754- p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 10, no 10, 754- p.
IdentifiersURN: urn:nbn:se:uu:diva-234588DOI: 10.15252/msb.20145114ISI: 000344595300005PubMedID: 25326100OAI: oai:DiVA.org:uu-234588DiVA: diva2:757203