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. Wefound 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 alsoinfluence long-range chromosomal contacts, demonstrating arole for natural genetic variation inchromosomal 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.