Dongwon Lee*, David U. Gorkin*, Maggie Baker, Benjamin J. Strober, Alessandro L. Asoni, Andrew S. McCallion†, Michael A. Beer†
*These authors contributed equally to this work.
†Correspondence should be addressed to: Mike Beer (mbeer AT jhu DOT edu)
Most variants implicated in common human disease by Genome-Wide Association Studies (GWAS) lie in non-coding sequence intervals. Despite the suggestion that regulatory element disruption represents a common theme, identifying causal risk variants within implicated genomic regions remains a major challenge. Here we present a new sequence-based computational method to predict the effect of regulatory variation, using a classifier (gkm-SVM) which encodes cell-specific regulatory sequence vocabularies. The induced change in the gkm-SVM score, deltaSVM, quantifies the effect of variants. We show that deltaSVM accurately predicts the impact of SNPs on DNase I sensitivity in their native genomic context and accurately predicts the results of dense mutagenesis of several enhancers in reporter assays. Previously validated GWAS SNPs yield large deltaSVM scores, and we predict new risk-conferring SNPs for several autoimmune diseases. Thus, deltaSVM provides a powerful computational approach to systematically identify functional regulatory variants.
If you have any questions, please contact Mike Beer at mbeer AT jhu DOT edu.
last updated: 7/2/2019