Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance

Abstract

Methods that analyze single-cell paired RNA-seq and ATAC-seq multiome data have shown great promise in linking regulatory elements to genes. However, existing methods differ in their modeling assumptions and approaches to account for biological and technical noise--leading to low concordance in their linking scores--and do not capture the effects of genomic distance. We propose pgBoost, an integrative modeling framework that trains a non-linear combination of existing linking strategies (including genomic distance) on fine-mapped eQTL data to assign a probabilistic score to each candidate SNP-gene link. We applied pgBoost to single-cell multiome data from 85k cells representing 6 major immune/blood cell types. pgBoost attained higher enrichment for fine-mapped eSNP-eGene pairs (e.g. 21x at distance >10kb) than existing methods (1.2-10x; p-value for difference = 5e-13 vs. distance-based method and 100kb; p-value for difference 10kb; p-value for difference = 0.25 vs. distance-based method and 100kb; p-value for difference < 0.009 for each other method). Similar improvements in enrichment were observed for links derived from Activity-By-Contact (ABC) scores and GWAS data. We further determined that restricting pgBoost to features from a focal cell type improved the identification of SNP-gene links relevant to that cell type. We highlight several examples where pgBoost linked fine-mapped GWAS variants to experimentally validated or biologically plausible target genes that were not implicated by other methods. In conclusion, a non-linear combination of linking strategies, including genomic distance, improves power to identify target genes underlying GWAS associations.