Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms
Abstract
Most disease associations detected by genome-wide association studies (GWAS) lie outside coding genes, but very few have been mapped to causal regulatory variants. Here, we present a method for detecting regulatory quantitative trait loci (QTLs) that does not require genotyping or whole-genome sequencing. The method combines deep, long-read chromatin immunoprecipitation-sequencing (ChIP-seq) with a statistical test that simultaneously scores peak height correlation and allelic imbalance: the genotype-independent signal correlation and imbalance (G-SCI) test. We performed histone acetylation ChIP-seq on 57 human lymphoblastoid cell lines and used the resulting reads to call 500,066 single-nucleotide polymorphisms de novo within regulatory elements. The G-SCI test annotated 8,764 of these as histone acetylation QTLs (haQTLs)—an order of magnitude larger than the set of candidates detected by expression QTL analysis. Lymphoblastoid haQTLs were highly predictive of autoimmune disease mechanisms. Thus, our method facilitates large-scale regulatory variant detection in any moderately sized cohort for which functional profiling data can be generated, thereby simplifying identification of causal variants within GWAS loci.
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- Authors
- del Rosario, R. C.-H., Poschmann, J., Rouam, S. L., Png, E., Khor, C. C., Hibberd, M. L., & Prabhakar, S.
- Affiliations
- Genome Institute of Singapore (SG)
- National University of Singapore (SG)
- London School of Hygiene & Tropical Medicine (GB)
- Corresponding author
- Prabhakar, Shyam
- Venue
- Nature Methods
- Published
- 2015-03-23
- Volume
- 12
- Issue
- 5
- Pages
- 458-464
- ISSN
- 1548-7091 (ISSN-L)
- 1548-7105
- OpenAlex
- W2144067586
- Cited by
- 58
- References
- 54
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 3 · 2019: 9 · 2018: 4 · 2017: 9 · 2016: 11 · 2015: 2 · 2014: 1
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Methods (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- HAL (submittedVersion)
- 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
- allelic imbalance, ChIP-seq, single nucleotide polymorphisms, lymphoblastoid cell lines, causal variant identification, epigenetic regulation
- MeSH terms
- Acetylation, Alleles, Cell Line, Gene Expression Regulation, Genetic Markers, Genotype, Histones, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcriptome
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