ena-STUDY-KTH-02-03-2018-12:29:04:921-475
Allele specific chromatin signals, 3D interactions and refined motif prediction for immune and B cell related diseases
Several Genome Wide Association Studies (GWAS) have reported variants associated to immune system diseases. However the identified variants are rarely the real drivers of the associations due to the heterogeneity in and between the study groups and most of the molecular mechanisms behind the genetic contributions to immune diseases remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs with significant allelespecific binding (AS-SNPs). These variants, which can affect a TF binding site resulting in altered gene regulation, are primary candidatesto explain associations observed in GWAS and expression studies. Results: We identified 17,293 unique AS-SNPs across 7 lymphoblastoidcell lines of which 237 were associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatorymechanisms we integrated long-range 3D interactions data (HiC and HiCap) to identify putative target genes and motif predictions based onParsimonious Markov Models (PMMs) to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPsassociated to gene expression and 60 to B cell related traits. Conclusions: We present a systems strategy to find functional gene regulatoryvariants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.
Several Genome Wide Association Studies (GWAS) have reported variants associated to immune system diseases. However the identified variants are rarely the real drivers of the associations due to the heterogeneity in and between the study groups and most of the molecular mechanisms behind the genetic contributions to immune diseases remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs with significant allelespecific binding (AS-SNPs). These variants, which can affect a TF binding site resulting in altered gene regulation, are primary candidatesto explain associations observed in GWAS and expression studies. Results: We identified 17,293 unique AS-SNPs across 7 lymphoblastoidcell lines of which 237 were associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatorymechanisms we integrated long-range 3D interactions data (HiC and HiCap) to identify putative target genes and motif predictions based onParsimonious Markov Models (PMMs) to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPsassociated to gene expression and 60 to B cell related traits. Conclusions: We present a systems strategy to find functional gene regulatoryvariants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.