title: Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk.
abstract: Cis-regulatory elements such as transcription factor (TF) binding sites can be identified genome-wide, but it remains far more challenging to pinpoint genetic variants affecting TF binding. Here, we introduce a pooling-based approach to mapping quantitative trait loci (QTLs) for molecular-level traits. Applying this to five TFs and a histone modification, we mapped thousands of cis-acting QTLs, with over 25-fold lower cost compared to standard QTL mapping. We found that single genetic variants frequently affect binding of multiple TFs, and CTCF can recruit all five TFs to its binding sites. These QTLs often affect local chromatin and transcription but can also influence long-range chromosomal contacts, demonstrating a role for natural genetic variation in chromosomal architecture. Thousands of these QTLs have been implicated in genome-wide association studies, providing candidate molecular mechanisms for many disease risk loci and suggesting that TF binding variation may underlie a large fraction of human phenotypic variation.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Tehranchi
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Marsha
authors.initials: M
authors.lastname: Myrthil
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Martin
authors.affiliation: Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hie
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Statistics, Stanford University, Stanford, CA 94305, USA.
authors.forename: David
authors.initials: D
authors.lastname: Golan
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: hbfraser@stanford.edu.
authors.forename: Hunter B
authors.initials: HB
authors.lastname: Fraser
mesh_terms: D047369:Chromatin Immunoprecipitation / Q000379:methods*; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D042421:Histone Code; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors