. 2022 Jun;54(6):772-782.

doi: 10.1038/s41588-022-01070-7. Epub 2022 May 30.

High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

Catherine Tcheandjieu^{1

2

3}, Ke Xiao⁴, Helio Tejeda¹, Julie A Lynch^{5

6}, Sanni Ruotsalainen⁷, Tiffany Bellomo^{8

9

10}, Madhuri Palnati¹¹, Renae Judy^{8

9}, Derek Klarin^{12

13}, Rachel L Kember^{8

14}, Shefali Verma¹⁵; Regeneron Genetics Center; VA Million Veterans Program; FinnGen Project; Aarno Palotie⁷, Mark Daly⁷, Marylyn Ritchie¹⁵, Daniel J Rader^{8

15}, Manuel A Rivas¹⁶, Themistocles Assimes^{2

3}, Philip Tsao^{2

3}, Scott Damrauer^{8

10}, James R Priest^{17

18

19}

Collaborators, Affiliations

Collaborators

Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Katia Karalis, Luca A Lotta, John D Overton, Jeffrey G Reid, Katherine Siminovitch, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiopoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D Schleicher, Louis Widom, Sarah E Wolf, Ricardo H Ulloa, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Deepika Sharma, Jeffrey C Staples, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J Mansfield, Evan K Maxwell, George Mitra, Mona Nafde, Sean O'Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Jiwen Xin, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Alexander Li, Nan Lin, Daren Liu, Adam Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Marcus B Jones, Jason Mighty, Lyndon J Mitnaul

Affiliations

¹ Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁴ MA College of Information & Computer Science, University of Massachusetts, Amherst, Amherst, MA, USA.
⁵ Veterans Affairs Informatics and Computing Infrastructure, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
⁶ University of Massachusetts College of Nursing & Health Sciences, Boston, MA, USA.
⁷ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁸ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁹ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
¹² VA Boston Healthcare System, Boston, MA, USA.
¹³ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷ Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA. jpriest@stanford.edu.
¹⁸ Chan-Zuckerberg Biohub, San Francisco, CA, USA. jpriest@stanford.edu.
¹⁹ Tenaya Therapeutics, South San Francisco, CA, USA. jpriest@stanford.edu.

PMID: 35637384
DOI: 10.1038/s41588-022-01070-7

High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

Catherine Tcheandjieu et al. Nat Genet. 2022 Jun.

. 2022 Jun;54(6):772-782.

doi: 10.1038/s41588-022-01070-7. Epub 2022 May 30.

Authors

Collaborators

Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris Economides, Katia Karalis, Luca A Lotta, John D Overton, Jeffrey G Reid, Katherine Siminovitch, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Maria Sotiopoulos Padilla, Manasi Pradhan, Kia Manoochehri, Thomas D Schleicher, Louis Widom, Sarah E Wolf, Ricardo H Ulloa, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Deepika Sharma, Jeffrey C Staples, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J Mansfield, Evan K Maxwell, George Mitra, Mona Nafde, Sean O'Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Jiwen Xin, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Eric Jorgenson, Hyun Min Kang, Michael Kessler, Jack Kosmicki, Alexander Li, Nan Lin, Daren Liu, Adam Locke, Jonathan Marchini, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Charles Paulding, Carlo Sidore, Eli Stahl, Kyoko Watanabe, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Marcus B Jones, Jason Mighty, Lyndon J Mitnaul

Affiliations

¹ Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁴ MA College of Information & Computer Science, University of Massachusetts, Amherst, Amherst, MA, USA.
⁵ Veterans Affairs Informatics and Computing Infrastructure, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT, USA.
⁶ University of Massachusetts College of Nursing & Health Sciences, Boston, MA, USA.
⁷ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁸ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁹ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, USA.
¹² VA Boston Healthcare System, Boston, MA, USA.
¹³ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷ Department of Pediatrics, Division of Pediatric Cardiology, Stanford University School of Medicine, Stanford, CA, USA. jpriest@stanford.edu.
¹⁸ Chan-Zuckerberg Biohub, San Francisco, CA, USA. jpriest@stanford.edu.
¹⁹ Tenaya Therapeutics, South San Francisco, CA, USA. jpriest@stanford.edu.

PMID: 35637384
DOI: 10.1038/s41588-022-01070-7

Abstract

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.

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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

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