title: Identifying causal regulatory SNPs in ChIP-seq enhancers.
abstract: Thousands of non-coding SNPs have been linked to human diseases in the past. The identification of causal alleles within this pool of disease-associated non-coding SNPs is largely impossible due to the inability to accurately quantify the impact of non-coding variation. To overcome this challenge, we developed a computational model that uses ChIP-seq intensity variation in response to non-coding allelic change as a proxy to the quantification of the biological role of non-coding SNPs. We applied this model to HepG2 enhancers and detected 4796 enhancer SNPs capable of disrupting enhancer activity upon allelic change. These SNPs are significantly over-represented in the binding sites of HNF4 and FOXA families of liver transcription factors and liver eQTLs. In addition, these SNPs are strongly associated with liver GWAS traits, including type I diabetes, and are linked to the abnormal levels of HDL and LDL cholesterol. Our model is directly applicable to any enhancer set for mapping causal regulatory SNPs.
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Huang
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA ovcharen@nih.gov.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ovcharenko
mesh_terms: D000483:Alleles; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004742:Enhancer Elements, Genetic; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors