DOI: 10.1101/474684Nov 20, 2018Paper

Annotations capturing cell-type-specific TF binding explain a large fraction of disease heritability

BioRxiv : the Preprint Server for Biology
Bryce van de GeijnAlkes L Price

Abstract

It is widely known that regulatory variation plays a major role in complex disease and that cell-type-specific binding of transcription factors (TF) is critical to gene regulation, but genomic annotations from directly measured TF binding information are not currently available for most cell-type-TF pairs. Here, we construct cell-type-specific TF binding annotations by intersecting sequence-based TF binding predictions with cell-type-specific chromatin data; this strategy 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 evaluated different combinations of sequence-based TF predictions and chromatin data by partitioning the heritability of 49 diseases and complex traits (average N=320K) using stratified LD score regression with the baseline-LD model (which is not cell-type-specific). We determined that 100bp 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 (1...Continue Reading

Related Concepts

Base Sequence
Chromatin
Genome
Signal Transduction
Transcription Factor
T-Cell Specificity
Protein Domain Specific Binding
Transcription Factor Binding
Genome Sequencing
Activated Lymphocyte

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