title: 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.
authors: Computational and Systems Biology Group, Genome Institute of Singapore, Singapore.
authors: Ricardo Cruz-Herrera
authors: RC
authors: del Rosario
authors: Computational and Systems Biology Group, Genome Institute of Singapore, Singapore.
authors: Jeremie
authors: J
authors: Poschmann
authors: Computational and Systems Biology Group, Genome Institute of Singapore, Singapore.
authors: Sigrid Laure
authors: SL
authors: Rouam
authors: Infectious Diseases Group, Genome Institute of Singapore, Singapore.
authors: Eileen
authors: E
authors: Png
authors: 1] Human Genetics Group, Genome Institute of Singapore, Singapore. [2] Singapore Eye Research Institute, Singapore. [3] Department of Opthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Chiea Chuen
authors: CC
authors: Khor
authors: 1] Infectious Diseases Group, Genome Institute of Singapore, Singapore. [2] Department of Pathogen Molecular Biology, London School of Hygiene &Tropical Medicine, London, UK.
authors: Martin Lloyd
authors: ML
authors: Hibberd
authors: Computational and Systems Biology Group, Genome Institute of Singapore, Singapore.
authors: Shyam
authors: S
authors: Prabhakar
mesh_terms: D000107:Acetylation; D000483:Alleles; D002460:Cell Line; D005786:Gene Expression Regulation; D005819:Genetic Markers; D005838:Genotype; D006657:Histones / Q000378:metabolism; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci; D059467:Transcriptome
chemical_list: D005819:Genetic Markers; D006657:Histones