Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk

•A pooling-based approach maps QTLs for molecular-level traits with reduced cost•Thousands of cis-acting QTLs affect transcription factor binding in humans•CTCF anchors binding of multiple transcription factors•Binding QTLs link genetic variation to 3D genome architecture and complex traits

SummaryCis-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.

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