In vivo measurement and prediction of cell-type-resolved non-coding variant effects in human immunity

Abstract

Interpreting non-coding variant effects in their native cellular context is the central problem in medical genomics. Using paired single-cell ATAC-seq and whole-genome sequencing in human immune cells, we measured allele-specific regulatory effects at 129,241 heterozygous variants across seven cell types. We trained REG-FOCUS, a transferable sequence-and-chromatin framework, and extended predictions to 1,188,417 common variants across twelve immune cell types. These predictions revealed that enhancer-centric variant directionality is governed by quantitative tuning of transcription factor binding affinity. Applied to systemic lupus erythematosus, REG-FOCUS prioritized causal regulatory variants selectively converging on pathways of approved therapies, and enabled us to identify rare enhancer variants in patients corroborated by expression outliers in carriers. This work brings cell-type-resolved variant interpretation to non-coding personal genomes.