Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart

X Rosa Ma; Stephanie D Conley; Michael Kosicki; Danila Bredikhin; Ran Cui; Steven Tran; Maya U Sheth; Wei-Lin Qiu; Sijie Chen; Soumya Kundu; Helen Y Kang; Dulguun Amgalan; Chad J Munger; Lauren Duan; Katherine Dang; Oriane Matthys Rubio; Shinwan Kany; Siavash Zamirpour; John DePaolo; Arun Padmanabhan; Birth Defects Research Laboratory; Jeffrey Olgin; Scott Damrauer; Robin Andersson; Mingxia Gu; James R Priest; Thomas Quertermous; Xiaojie Qiu; Marlene Rabinovitch; Axel Visel; Len Pennacchio; Anshul Kundaje; Ian A Glass; Casey A Gifford; James P Pirruccello; William R Goodyer; Jesse M Engreitz

doi:10.1101/2024.11.20.24317557

Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart

medRxiv [Preprint]. 2024 Nov 22:2024.11.20.24317557. doi: 10.1101/2024.11.20.24317557.

Authors

X Rosa Ma^{1

2}, Stephanie D Conley^{1

2}, Michael Kosicki³, Danila Bredikhin^{1

2}, Ran Cui^{4

5

6

7}, Steven Tran⁸, Maya U Sheth^{1

2

9}, Wei-Lin Qiu^{7

10}, Sijie Chen^{1

2

11}, Soumya Kundu^{2

11}, Helen Y Kang^{1

2

12}, Dulguun Amgalan^{1

2

13}, Chad J Munger^{1

2}, Lauren Duan⁸, Katherine Dang⁸, Oriane Matthys Rubio^{1

8}, Shinwan Kany^{14

15

16

17}, Siavash Zamirpour¹⁸, John DePaolo¹⁹, Arun Padmanabhan^{20

21

22}; Birth Defects Research Laboratory; Jeffrey Olgin²³, Scott Damrauer^{24

25

26

27}, Robin Andersson^{7

10}, Mingxia Gu^{28

29}, James R Priest^{8

30}, Thomas Quertermous^{2

31

32}, Xiaojie Qiu^{1

2

11

13

32

33}, Marlene Rabinovitch^{1

8

32

34}, Axel Visel^{3

35

36}, Len Pennacchio^{3

35

37}, Anshul Kundaje^{2

11}, Ian A Glass^{13

38}, Casey A Gifford^{1

2

8

13

32

39}, James P Pirruccello^{14

23

40

41}, William R Goodyer^{8

13

32}, Jesse M Engreitz^{1

2

7

13

32

42}

Affiliations

¹ Basic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
² Department of Genetics, Stanford University, Stanford, CA, USA.
³ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Pediatrics, Stanford University, Stanford, CA, USA.
⁹ Department of Bioengineering, Stanford University, Stanford, CA, USA.
¹⁰ Department of Biology, University of Copenhagen, Copenhagen, Denmark.
¹¹ Department of Computer Science, Stanford University, Stanford, CA, USA.
¹² Current address: PhD Program in Computational and Systems Biology, MIT, Cambridge, MA, USA.
¹³ Maternal and Child Health Research Institute, Stanford University, Stanford, CA, USA.
¹⁴ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁵ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Department of Cardiology, University Heart and Vascular Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁷ German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany.
¹⁸ School of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁹ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁰ Gladstone Institutes, San Francisco, CA, USA.
²¹ Department of Medicine, University of California San Francisco School of Medicine, San Francisco, CA, USA.
²² Chan Zuckerberg Biohub, San Francisco, CA, USA.
²³ Division of Cardiology, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
²⁴ Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
²⁷ Penn Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁸ Center for Stem Cell and Organoid Medicine, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²⁹ University of Cincinnati School of Medicine, Cincinnati, OH, USA.
³⁰ Tenaya Therapeutics, South San Francisco, CA, USA.
³¹ Department of Medicine, Stanford University, Stanford, CA, USA.
³² Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
³³ Stanford Bio-X, Stanford University, Stanford, CA, USA.
³⁴ Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University, Stanford, CA, USA.
³⁵ US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
³⁶ School of Natural Sciences, University of California, Merced, Merced, CA, USA.
³⁷ Comparative Biochemistry Program, University of California, Berkeley, CA, 94720, USA.
³⁸ Department of Pediatrics and Medicine, University of Washington School of Medicine, Seattle, WA, USA.
³⁹ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁴⁰ Institute for Human Genetics, University of California, San Francisco, CA, USA.
⁴¹ Bakar Computation Health Sciences Institute, University of California, San Francisco, CA, USA.
⁴² Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Abstract

Congenital heart defects (CHD) arise in part due to inherited genetic variants that alter genes and noncoding regulatory elements in the human genome. These variants are thought to act during fetal development to influence the formation of different heart structures. However, identifying the genes, pathways, and cell types that mediate these effects has been challenging due to the immense diversity of cell types involved in heart development as well as the superimposed complexities of interpreting noncoding sequences. As such, understanding the molecular functions of both noncoding and coding variants remains paramount to our fundamental understanding of cardiac development and CHD. Here, we created a gene regulation map of the healthy human fetal heart across developmental time, and applied it to interpret the functions of variants associated with CHD and quantitative cardiac traits. We collected single-cell multiomic data from 734,000 single cells sampled from 41 fetal hearts spanning post-conception weeks 6 to 22, enabling the construction of gene regulation maps in 90 cardiac cell types and states, including rare populations of cardiac conduction cells. Through an unbiased analysis of all 90 cell types, we find that both rare coding variants associated with CHD and common noncoding variants associated with valve traits converge to affect valvular interstitial cells (VICs). VICs are enriched for high expression of known CHD genes previously identified through mapping of rare coding variants. Eight CHD genes, as well as other genes in similar molecular pathways, are linked to common noncoding variants associated with other valve diseases or traits via enhancers in VICs. In addition, certain common noncoding variants impact enhancers with activities highly specific to particular subanatomic structures in the heart, illuminating how such variants can impact specific aspects of heart structure and function. Together, these results implicate new enhancers, genes, and cell types in the genetic etiology of CHD, identify molecular convergence of common noncoding and rare coding variants on VICs, and suggest a more expansive view of the cell types instrumental in genetic risk for CHD, beyond the working cardiomyocyte. This regulatory map of the human fetal heart will provide a foundational resource for understanding cardiac development, interpreting genetic variants associated with heart disease, and discovering targets for cell-type specific therapies.

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Abstract

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