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

Adam W Turner; Shengen Shawn Hu; Jose Verdezoto Mosquera; Wei Feng Ma; Chani J Hodonsky; Doris Wong; Gaëlle Auguste; Yipei Song; Katia Sol-Church; Emily Farber; Soumya Kundu; Anshul Kundaje; Nicolas G Lopez; Lijiang Ma; Saikat Kumar B Ghosh; Suna Onengut-Gumuscu; Euan A Ashley; Thomas Quertermous; Aloke V Finn; Nicholas J Leeper; Jason C Kovacic; Johan L M Björkegren; Chongzhi Zang; Clint L Miller

doi:10.1038/s41588-022-01069-0

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

Nat Genet. 2022 Jun;54(6):804-816. doi: 10.1038/s41588-022-01069-0. Epub 2022 May 19.

Authors

Adam W Turner^#¹, Shengen Shawn Hu^#¹, Jose Verdezoto Mosquera^{1

2}, Wei Feng Ma^{1

3

4}, Chani J Hodonsky^{1

5}, Doris Wong^{1

2

5}, Gaëlle Auguste¹, Yipei Song¹, Katia Sol-Church^{4

6}, Emily Farber^{1

7}, Soumya Kundu⁸, Anshul Kundaje^{8

9}, Nicolas G Lopez¹⁰, Lijiang Ma¹¹, Saikat Kumar B Ghosh¹², Suna Onengut-Gumuscu^{1

7

13}, Euan A Ashley^{8

14}, Thomas Quertermous¹⁴, Aloke V Finn¹², Nicholas J Leeper¹⁰, Jason C Kovacic^{15

16

17}, Johan L M Björkegren^{11

18}, Chongzhi Zang^{19

20

21}, Clint L Miller^{22

23

24

25}

Affiliations

¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
² Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
³ Medical Scientist Training Program, University of Virginia, Charlottesville, VA, USA.
⁴ Department of Pathology, University of Virginia, Charlottesville, VA, USA.
⁵ Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
⁶ Genome Analysis & Technology Core, University of Virginia, Charlottesville, VA, USA.
⁷ Genome Sciences Laboratory, University of Virginia, Charlottesville, VA, USA.
⁸ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Computer Science, Stanford University, Stanford, CA, USA.
¹⁰ Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, CA, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² CVPath Institute, Gaithersburg, MD, USA.
¹³ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹⁴ Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁵ Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
¹⁷ St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
¹⁸ Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Huddinge, Sweden.
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. [email protected].
²⁰ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA. [email protected].
²¹ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. [email protected].
²² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. [email protected].
²³ Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA. [email protected].
²⁴ Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA. [email protected].
²⁵ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Chromatin / genetics
Coronary Artery Disease* / genetics
Coronary Artery Disease* / metabolism
Genome-Wide Association Study*
Humans
Polymorphism, Single Nucleotide / genetics
Transcription Factors / genetics

Substances

Chromatin
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding