Journal article Open Access

Context-dependent epigenomic weighting improves identification of regulatory variants and disease-associated genes

Mulin Jun Li

cepip: Context-dependent epigenomic weighting for regulatory variant prioritization

Majority of trait/disease associated variants identified by genome wide association studies (GWASs) locate in the regulatory regions. Since gene regulation is highly context-specific, it remains challenging to fine-map and prioritize functional regulatory variants in a particular cell/tissue type and apply them to disease-associated genes detection. By connecting large-scale epigenome profiles to expression quantitative trait loci (eQTLs) in a wide range of human tissues/cell types, we identify combination of several critical chromatin features that predict variant regulatory potential. We develop a joint likelihood framework to measure the regulatory probability of genetic variants in a context-dependent manner. We show our model is superior to existing cell type-specific methods and exhibit significant GWAS signal enrichment. Using phenotypically relevant epigenomes to weight GWAS SNPs, we discover more disease-associated genes owing to regulatory changes and improve the statistical power in gene-based association test.

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