PT  - JOURNAL ARTICLE
AU  - Gregory A. Moyerbrailean
AU  - Chris T. Harvey
AU  - Cynthia A. Kalita
AU  - Xiaoquan Wen
AU  - Francesca Luca
AU  - Roger Pique-Regi
TI  - Are all genetic variants in DNase I sensitivity regions functional?
AID  - 10.1101/007559
DP  - 2014 Jan 01
TA  - bioRxiv
PG  - 007559
4099  - http://biorxiv.org/content/early/2014/07/29/007559.short
4100  - http://biorxiv.org/content/early/2014/07/29/007559.full
AB  - A detailed mechanistic understanding of the direct functional consequences of DNA variation on gene regulatory mechanism is critical for a complete understanding of complex trait genetics and evolution. Here, we present a novel approach that integrates sequence information and DNase I footprinting data to predict the impact of a sequence change on transcription factor binding. Applying this approach to 653 DNase-seq samples, we identified 3,831,862 regulatory variants predicted to affect active regulatory elements for a panel of 1,372 transcription factor motifs. Using QuASAR, we validated the non-coding variants predicted to be functional by examining allele-specific binding (ASB). Combining the predictive model and the ASB signal, we identified 3,217 binding variants within footprints that are significantly imbalanced (20% FDR). Even though most variants in DNase I hyper-sensitive regions may not be functional, we estimate that 56% of our annotated functional variants show actual evidence of ASB. To assess the effect these variants may have on complex phenotypes, we examined their association with complex traits using GWAS and observed that ASB-SNPs are enriched 1.22-fold for complex traits variants. Furthermore, we show that integrating footprint annotations into GWAS meta-study results improves identification of likely causal SNPs and provides a putative mechanism by which the phenotype is affected.