@article{f20f8a45b731424ea3dafb31dbc39d63,
title = "Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk",
abstract = "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.",
author = "Turner, {Adam W.} and Hu, {Shengen Shawn} and Mosquera, {Jose Verdezoto} and Ma, {Wei Feng} and Hodonsky, {Chani J.} and Doris Wong and Ga{\"e}lle Auguste and Yipei Song and Katia Sol-Church and Emily Farber and Soumya Kundu and Anshul Kundaje and Lopez, {Nicolas G.} and Lijiang Ma and Ghosh, {Saikat Kumar B.} and Suna Onengut-Gumuscu and Ashley, {Euan A.} and Thomas Quertermous and Finn, {Aloke V.} and Leeper, {Nicholas J.} and Kovacic, {Jason C.} and Bj{\"o}rkgren, {Johan L.M.} and Chongzhi Zang and Miller, {Clint L.}",
note = "Funding Information: J.L.M.B. is a shareholder in Clinical Gene Network AB who have a vested interest in STARNET. A.V.F. at CVPath also acknowledges receiving financial support from the following entities: 4C Medical, 4Tech, Abbott Vascular, Ablative Solutions, Absorption Systems, Advanced NanoTherapies, Aerwave Medical, Alivas, Amgen, Asahi Medical, Aurios Medical, Avantec Vascular, BD, Biosensors, Biotronik, Biotyx Medical, Bolt Medical, Boston Scientific, Canon, Cardiac Implants, Cardiawave, CardioMech, Cardionomic, Celonova, Cerus, EndoVascular, Chansu Vascular Technologies, Children{\textquoteright}s National, Concept Medical, Cook Medical, Cooper Health, Cormaze, CRL, Croivalve, CSI, Dexcom, Edwards Lifesciences, Elucid Bioimaging, eLum Technologies, Emboline, Endotronix, Envision, Filterlex, Imperative Care, Innovalve, Innovative, Cardiovascular Solutions, Intact Vascular, Interface Biolgics, Intershunt Technologies, Invatin, Lahav, Limflow, L&J Bio, Lutonix, Lyra Therapeutics, Mayo Clinic, Maywell, MDS, MedAlliance, Medanex, Medtronic, Mercator, Microport, Microvention, Neovasc, Nephronyx, Nova Vascular, Nyra Medical, Occultech, Olympus, Ohio Health, OrbusNeich, Ossio, Phenox, Pi-Cardia, Polares Medical, Polyvascular, Profusa, ProKidney, LLC, Protembis, Pulse Biosciences, Qool Therapeutics, Recombinetics, Recor Medical, Regencor, Renata Medical, Restore Medical, Ripple Therapeutics, Rush University, Sanofi, Shockwave, SMT, SoundPipe, Spartan Micro, Spectrawave, Surmodics, Terumo Corporation, The Jacobs Institute, Transmural Systems, Transverse Medical, TruLeaf, UCSF, UPMC, Vascudyne, Vesper, Vetex Medical, Whiteswell, WL Gore, Xeltis. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The other authors declare no competing interests. Funding Information: This work was supported by grants from: the National Institutes of Health (grant nos. R01HL148239 and R00HL125912 to C.L.M.; grant no. R35GM133712 to C.Z.; grant no. R01HL141425 to A.V.F.; grant no. R01HL125863 to J.L.M.B.; grant nos. R01HL130423, R01HL135093 and R01HL148167-01A1 to J.C.K.; grant nos. R35HL144475, R01HL125224, R01HL134817 and R01HL139478 to T.Q.; and grant no. R01HL123370 to N.J.L.), the American Heart Association (grant no. 20POST35120545 to A.W.T.; grant no. A14SFRN20840000 to J.L.M.B.; grant no. 19EIA34770065 to N.J.L.), the Swedish Research Council and Heart Lung Foundation (grant nos. 2018-02529 and 20170265 to J.L.M.B.) and the Fondation Leducq (grant no. {\textquoteleft}PlaqOmics{\textquoteright} 18CVD02 to N.J.L., J.L.M.B., A.V.F. and C.L.M.). We thank P. Chiu, P. Chang and M. Wong at Stanford University for surgical assistance and research donor heart procurement. We thank T. Koyano at Stanford University for assistance in extracting clinical information. We thank all of the transplant recipients and heart donors, family members, study coordinators and the transplant tissue procurement team at Stanford. We thank B. Liu and N. Kumasaka for helpful discussions on QTL scripts. Finally, we thank P. Pramoonjago and S. VanHoose at the University of Virginia for histological support and all staff of the core facilities for tissue processing, library construction and sequencing assistance. Funding Information: This work was supported by grants from: the National Institutes of Health (grant nos. R01HL148239 and R00HL125912 to C.L.M.; grant no. R35GM133712 to C.Z.; grant no. R01HL141425 to A.V.F.; grant no. R01HL125863 to J.L.M.B.; grant nos. R01HL130423, R01HL135093 and R01HL148167-01A1 to J.C.K.; grant nos. R35HL144475, R01HL125224, R01HL134817 and R01HL139478 to T.Q.; and grant no. R01HL123370 to N.J.L.), the American Heart Association (grant no. 20POST35120545 to A.W.T.; grant no. A14SFRN20840000 to J.L.M.B.; grant no. 19EIA34770065 to N.J.L.), the Swedish Research Council and Heart Lung Foundation (grant nos. 2018-02529 and 20170265 to J.L.M.B.) and the Fondation Leducq (grant no. {\textquoteleft}PlaqOmics{\textquoteright} 18CVD02 to N.J.L., J.L.M.B., A.V.F. and C.L.M.). We thank P. Chiu, P. Chang and M. Wong at Stanford University for surgical assistance and research donor heart procurement. We thank T. Koyano at Stanford University for assistance in extracting clinical information. We thank all of the transplant recipients and heart donors, family members, study coordinators and the transplant tissue procurement team at Stanford. We thank B. Liu and N. Kumasaka for helpful discussions on QTL scripts. Finally, we thank P. Pramoonjago and S. VanHoose at the University of Virginia for histological support and all staff of the core facilities for tissue processing, library construction and sequencing assistance. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jun,
doi = "10.1038/s41588-022-01069-0",
language = "English",
volume = "54",
pages = "804--816",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group - Macmillan Publishers",
number = "6",
}