Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability
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Le résumé fourni par la source
Regulatory variation plays a major role in complex disease and that cell type-specific binding of transcription factors (TF) is critical to gene regulation. However, assessing the contribution of genetic variation in TF-binding sites to disease heritability is challenging, as binding is often cell type-specific and annotations from directly measured TF binding are not currently available for most cell type-TF pairs. We investigate approaches to annotate TF binding, including directly measured chromatin data and sequence-based predictions. We find that TF-binding annotations constructed by intersecting sequence-based TF-binding predictions with cell type-specific chromatin data explain a large fraction of heritability across a broad set of diseases and corresponding cell types; this strategy of constructing annotations addresses both the limitation that identical sequences may be bound or unbound depending on surrounding chromatin context and the limitation that sequence-based predictions are generally not cell type-specific. We partitioned the heritability of 49 diseases and complex traits using stratified linkage disequilibrium (LD) score regression with the baseline-LD model (which is not cell type-specific) plus the new annotations. We determined that 100 bp windows around MotifMap sequenced-based TF-binding predictions intersected with a union of six cell type-specific chromatin marks (imputed using ChromImpute) performed best, with an 58% increase in heritability enrichment compared to the chromatin marks alone (11.6× vs. 7.3×, P = 9 × 10-14 for difference) and a 20% increase in cell type-specific signal conditional on annotations from the baseline-LD model (P = 8 × 10-11 for difference). Our results show that TF-binding annotations explain substantial disease heritability and can help refine genome-wide association signals.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability
- Date Crossref
- 09/10/2019
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
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Harvard University Department of Computer Science pays non établi dans la noticeUniversité ou école supérieure
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Broad Institute Program in Medical and Population Genetics pays non établi dans la noticeOrganisation à but non lucratif
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Brigham and Women's Hospital Department of Medicine pays non établi dans la noticeÉtablissement de santé
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Center for Systems Biology pays non établi dans la noticeStructure de recherche
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Dana-Farber Cancer Institute pays non établi dans la noticeStructure de recherche
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University of California Bioinformatics Interdepartmental Program pays non établi dans la noticeUniversité ou école supérieure
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Harvard T.H. Chan School of Public Health Department of Epidemiology pays non établi dans la noticeUniversité ou école supérieure
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Department of Computer Science — Harvard University, Program in Medical and Population Genetics — Broad Institute et Department of Medicine — Brigham and Women's Hospital, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.