Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk
Open accessAbstract
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.
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Genetic variants associated with differential binding of PU.1 underpin GWAS variants associated with blood cell count and autoimmune diseases.
“For example, genetic variants associated with differential binding of PU.1 were found to underpin GWAS variants associated with blood cell count and autoimmune diseases [213–215].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [214]
In Results, under “bQTLs provide candidate molecular mechanisms for thousands of GWAS-implicated variants” (page unavailable), the paper identifies PU.1 binding QTLs linked to Crohn’s disease, inflammatory bowel disease, atopic dermatitis, and asthma GWAS loci. Our copy does not identify a PU.1 binding variant linked to blood cell count, and presents the disease mechanisms as candidates rather than established causes. (LLM, conf=0.85)
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- Authors
- Tehranchi, A. K., Myrthil, M., Martin, T., Hie, B. L., Golan, D., & Fraser, H. B.
- Affiliations
- Stanford University (US)
- University of Chicago (US)
- Corresponding author
- Fraser, Hunter B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 165
- Issue
- 3
- Pages
- 730-741
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4842172
- OpenAlex
- W2341698020
- Cited by
- 120
- References
- 12
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 16 · 2023: 11 · 2022: 16 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 12 · 2017: 15 · 2016: 7
- FWCI
- 7.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (1DP2OD008456-01, T32GM007276)
- NSF
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- transcription factor binding sites, cis-regulatory elements, quantitative trait loci, genetic variation, CTCF, histone modifications, chromatin structure, phenotypic variability, disease risk loci
- MeSH terms
- Humans, Transcription Factors, Sequence Analysis, DNA, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Histone Code, Chromatin Immunoprecipitation, High-Throughput Nucleotide Sequencing
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