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Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0001-8505-403x
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2695Article in journal (Refereed) Published
Abstract [en]

Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 2695
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Medical Genetics
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URN: urn:nbn:se:uu:diva-379258DOI: 10.1038/s41598-019-39633-0ISI: 000459571100059PubMedID: 30804403OAI: oai:DiVA.org:uu-379258DiVA, id: diva2:1296414
Funder
Swedish Research Council, 78081Swedish National Infrastructure for Computing (SNIC)EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationErnfors FoundationSwedish Cancer Society, 160518German Research Foundation (DFG), GR-3526/1German Research Foundation (DFG), GR-3526/2Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved

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Cavalli, MarcoBaltzer, NicholasUmer, Husen MuhammadPan, GangWallerman, OlaKomorowski, JanWadelius, Claes

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