A method to predict the impact of regulatory variants from DNA sequence

Dongwon Lee, David U. Gorkin, Maggie Baker, Benjamin J. Strober, Alessandro L. Asoni, Andrew S. McCallion, Michael A. Beer

Research output: Contribution to journalArticlepeer-review

211 Scopus citations


Most variants implicated in common human disease by genome-wide association studies (GWAS) lie in noncoding 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) that encodes cell type-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 contexts 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.

Original languageEnglish (US)
Pages (from-to)955-961
Number of pages7
JournalNature genetics
Issue number8
StatePublished - Aug 30 2015

ASJC Scopus subject areas

  • Genetics


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