Genetic integration reveals causal effects of chromatin accessibility on nucleosome positioning across diverse muscle cells

Cell type-specific chromatin accessibility QTL (caQTL) mapping is a promising approach to understand genetic control of chromatin landscapes and identify regulatory mechanisms underlying GWAS associations. However, current caQTL studies lack resolution and do not distinguish nucleosome-free regions (NFR) from positioned nucleosomes. Here, we leverage statistical modeling of fragment position and length to decompose ATAC-seq profiles into NFRs and phased nucleosomes. With single nucleus (sn)ATAC-seq from 281 human muscle biopsies, we map cell type-specific genetic effects on NFRs (76,027 nfrQTLs) and nucleosome occupancy (24,623 nucQTLs) across skeletal muscle cell types. Colocalization and causal inference analyses identify 1,528 instances where nfrQTLs have likely causal effects on adjacent nucleosome positioning, supporting a causal relationship in shaping chromatin profiles. 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 approach adds mechanistic insights for how variants underlying skeletal muscle caQTLs and GWAS signals exert their cis regulatory effects by initially modifying NFR accessibility and subsequently shaping broader chromatin landscapes, nucleosome positioning, gene expression, and ultimately higher-level traits and disease. Chromatin accessibility QTLs can reveal how genetic variants influence gene regulation, but the role of nucleosome organisation remains unclear. Here, the authors map genetic effects on nucleosome‑free regions and positioned nucleosomes in human skeletal muscle, linking regulatory variants to chromatin architecture and disease-associated traits.