Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk
Nat Genet.. 2022-06-01;54(6):804-816.
- Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing 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 and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- 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.
- Consortium data used in this publication
- All raw and processed single-nucleus chromatin accessibility sequencing datasets are made available on the Gene Expression Omnibus (GEO) database (accessions codes GSE175621 and GSE188422). The processed and analyzed snATAC-seq data will also be made available on the PlaqView single-cell data portal (https://www.plaqview.com). All caQTL data are available in the Supplementary Data. Low-pass whole-genome sequencing-based genotyping data are available on dbGaP (accession code phs002855.v1.p1). The human coronary artery scRNA-seq dataset we used in this study from Wirka et al. is available through GEO (accession code GSE131778). The mouse atherosclerosis scRNA-seq dataset from Pan et al. is available through GEO (accession code GSE155513). The reprocessed and analyzed human and mouse datasets are also available on PlaqView. Gene expression levels, expression quantitative trait locus (eQTL) data and eQTL boxplots were obtained from the Genotype-Tissue Expression (GTEx) v.8 portal website (https://www.gtexportal.org), GEO and HeartBioPortal (www.heartbioportal.com). Gene regulatory network analysis data from the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) are available at http://starnet.mssm.edu.
- DSR575ALX, DSR702NJX, DSR868SOF, DSR077AGV, DSR375DYB, DSR860LQT, DSR934MUL, DSR375BRX, DSR585FEK, DSR081PPK, DSR899CVG, DSR546OGW, DSR155WWW, DSR376XUQ, DSR482YKK, DSR820HFH, DSR136KQZ, DSR975AHF, DSR775NSC, DSR722SJM, DSR645IYA, DSR624IXR, DSR183JOK, DSR159KWW, DSR324HBV, DSR882ZAM, DSR819PVG, DSR852BMD, DSR109WKW, DSR661UXX, DSR497NBU, DSR138GQR, DSR928POW, DSR030DLE, DSR381VES, DSR299XCE, DSR019GTJ, DSR508WPI, DSR493MDX, DSR838SFW, DSR988JZQ
- File format
- Data summary
- Supplementary Data 6 Chromatin accessibility QTLs within individual coronary artery cell types, calculated using RASQUAL.
- File format
- Data summary
- Supplementary Data 7 Chromatin accessibility QTLs from bulk coronary artery ATAC-seq data, calculated using RASQUAL.