Rxivist logo

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

By Bryce van de Geijn, Hilary Finucane, Steven Gazal, Farhad Hormozdiari, Tiffany Amariuta, Xuanyao Liu, Alexander Gusev, Po-Ru Loh, Yakir A Reshef, Gleb Kichaev, Soumya Raychauduri, Alkes Price

Posted 20 Nov 2018
bioRxiv DOI: 10.1101/474684

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 (11.6x vs 7.3x; P = 9 x 10-14 for difference) and a 12% increase in cell-type-specific signal conditional on annotations from the baseline-LD model (P = 8 x 10-11 for difference). Our results show that intersecting sequence-based TF predictions with cell-type-specific chromatin information can help refine genome-wide association signals.

Download data

  • Downloaded 706 times
  • Download rankings, all-time:
    • Site-wide: 49,060
    • In genetics: 2,070
  • Year to date:
    • Site-wide: 129,935
  • Since beginning of last month:
    • Site-wide: 150,613

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide