Genetic integration with cell-specific nucleosome positioning resolves causal relationships underlying chromatin accessibility profiles

Cell type-specific chromatin accessibility QTL (caQTL) mapping is a promising approach for understanding genetic control of chromatin landscapes and identifying regulatory mechanisms underlying GWAS associations. However, current caQTL studies do not distinguish nucleosome-free regions (NFR) from positioned nucleosomes. Here, we leverage ATAC-seq fragment position and length to decompose accessible chromatin into NFRs and phased nucleosomes. With snATAC-seq from 281 muscle biopsies, we map cell type-specific genetic effects on NFR accessibility (76,027 nfrQTLs) and nucleosome occupancy (24,623 nucQTLs) across five skeletal muscle cell types. We find abundant colocalization between nucQTLs and nearby nfrQTLs and show that nfrQTLs are substantially more likely to causally influence nucQTLs than the other way around. Hundreds of nfrQTLs colocalize with GWAS signals for muscle-related traits, including grip strength, atrial fibrillation, and fasting insulin, and the majority of colocalizing signals mapped to credible sets overlapping the corresponding nfrPeak. This method elucidates how variants underlying caQTLs and GWAS signals exert their cis regulatory effects by initially modifying NFR accessibility and subsequently shaping broader chromatin landscapes, gene expression, and ultimately higher-level traits and disease.