Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies (GWAS) have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements (CREs). Here, we applied single-nucleus ATAC-seq to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants. . We identified elements in smooth muscle cell (SMC) transition states (e.g. fibromyocytes) and functional variants predicted to alter SMC and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.