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Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2014 (English)In: Molecular Systems Biology, ISSN 1744-4292, Vol. 10, no 10, 754- p.Article in journal (Refereed) Published
Abstract [en]

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.
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-234588DOI: 10.15252/msb.20145114ISI: 000344595300005PubMedID: 25326100OAI: diva2:757203
Available from: 2014-10-21 Created: 2014-10-21 Last updated: 2014-12-16Bibliographically approved

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Carlsson Almlöf, JonasLundmark, PerRönnblom, LarsSyvänen, Ann-Christine
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