期刊
NATURE GENETICS
卷 47, 期 8, 页码 955-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3331
关键词
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资金
- US National Institutes of Health [R01 NS62972, R01 HG007348]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG007348] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [K12GM068524, T32GM007814] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS062972] Funding Source: NIH RePORTER
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.
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