Heritability enrichment in context-specific regulatory networks improves phenotype-relevant tissue identification

Systems genetics holds the promise to decipher complex traits by interpreting their associated SNPs through gene regulatory networks derived from comprehensive multi-omics data of cell types, tissues, and organs. Here, we propose SpecVar to integrate paired chromatin accessibility and gene expression data into context-specific regulatory network atlas and regulatory categories, conduct heritability enrichment analysis with GWAS summary statistics, identify relevant tissues, and depict shared heritability and regulations by relevance correlation. Our method improves power upon existing approaches by associating SNPs with context-specific regulatory elements to assess heritability enrichments and by explicitly prioritizing gene regulations underlying relevant tissues. Experiments on GWAS of six phenotypes show that SpecVar can improve heritability enrichment, accurately detect relevant tissues, and reveal causal regulations. Furthermore, SpecVar correlates the relevance patterns for pairs of phenotypes and better reveals shared heritability and regulations of phenotypes than existing methods. Studying GWAS of 206 phenotypes in UK-Biobank demonstrates that SpecVar leverages the context-specific regulatory network atlas to prioritize phenotypes relevant tissues and shared heritability for biological and therapeutic insights. SpecVar provides a powerful way to interpret SNPs via context-specific regulatory networks and is available at https://github.com/AMSSwanglab/SpecVar.