Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program.

Humans Genome-Wide Association Study Veterans Pedigree Aortic Aneurysm, Thoracic / genetics Aortic Dissection / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
07 2023
Historique:
received: 04 04 2022
accepted: 05 05 2023
medline: 13 7 2023
pubmed: 13 6 2023
entrez: 12 6 2023
Statut: ppublish

Résumé

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

Identifiants

DOI: 10.1038/s41588-023-01420-z PMID: 37308786 PMC: PMC10335930
pubmed: 37308786
doi: 10.1038/s41588-023-01420-z
pii: 10.1038/s41588-023-01420-z
pmc: PMC10335930
mid: NIHMS1912946
doi:

Substances chimiques

1,3,4,6-tetra-O-acetyl-2-azido-2-deoxyglucopyranose 80321-89-7

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1106-1115

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL143359
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139731
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL109946
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151283
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM124836
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL092577
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG011719
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127564
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001780
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151152
Pays : United States
Organisme : BLRD VA
ID : IK2 BX005759
Pays : United States
Organisme : NIDDK NIH HHS
ID : F30 DK120062
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL158157
Pays : United States
Organisme : BLRD VA
ID : I01 BX003362
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007843
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL155915
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148050
Pays : United States
Organisme : Wellcome Trust
ID : 100114
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL109942
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159988
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL159346
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL062594
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139865
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007208
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142711
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157635
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL153937
Pays : United States

Informations de copyright

© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Références

J Biol Chem. 2010 Feb 12;285(7):4870-82
pubmed: 19940141
Nat Genet. 2013 Nov;45(11):1345-52
pubmed: 24097064
Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):155-62
pubmed: 25395615
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Thromb Haemost. 2013 Jan;109(1):79-84
pubmed: 23178976
Bioinformatics. 2017 Jan 15;33(2):272-279
pubmed: 27663502
Hum Mol Genet. 2015 Jun 15;24(12):3305-13
pubmed: 25743184
Nat Commun. 2021 Dec 8;12(1):7117
pubmed: 34880243
Circulation. 2006 Nov 21;114(21):2226-31
pubmed: 17101856
Eur Heart J. 2014 Nov 1;35(41):2873-926
pubmed: 25173340
Nat Metab. 2021 Apr;3(4):469-484
pubmed: 33846639
Nat Genet. 2022 May;54(5):573-580
pubmed: 35513724
Science. 2003 Apr 11;300(5617):329-32
pubmed: 12690199
Nat Biotechnol. 2013 Dec;31(12):1102-10
pubmed: 24270849
Nat Genet. 2019 Apr;51(4):675-682
pubmed: 30926970
Nat Genet. 2016 Mar;48(3):245-52
pubmed: 26854917
Nat Genet. 2014 Nov;46(11):1173-86
pubmed: 25282103
Nat Genet. 2011 Sep 11;43(10):996-1000
pubmed: 21909107
Nat Genet. 2022 Jan;54(1):40-51
pubmed: 34837083
Nature. 2017 Feb 9;542(7640):186-190
pubmed: 28146470
J Am Coll Cardiol. 2018 Aug 7;72(6):605-615
pubmed: 30071989
JAMA Cardiol. 2018 Jan 1;3(1):26-33
pubmed: 29188294
Am J Hum Genet. 2016 Sep 1;99(3):762-769
pubmed: 27569546
Atherosclerosis. 2014 Feb;232(2):361-8
pubmed: 24468149
Psychol Med. 2020 Oct;50(14):2435-2443
pubmed: 31689377
Front Digit Health. 2020 Aug 11;2:14
pubmed: 34713027
Circulation. 2020 Oct 6;142(14):1374-1388
pubmed: 33017217
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Circulation. 1992 Jan;85(1):205-11
pubmed: 1728451
Elife. 2018 May 30;7:
pubmed: 29846171
Bioinformatics. 2010 May 1;26(9):1205-10
pubmed: 20335276
Epidemiology. 2017 Jan;28(1):30-42
pubmed: 27749700
Science. 2000 Sep 1;289(5484):1501-4
pubmed: 10968779
Anat Rec. 2000 Jan 1;258(1):1-14
pubmed: 10603443
Nat Genet. 2013 Nov;45(11):1274-1283
pubmed: 24097068
PLoS One. 2021 Sep 1;16(9):e0247287
pubmed: 34469433
Circulation. 2021 Aug 3;144(5):353-364
pubmed: 34139859
Int J Epidemiol. 2015 Apr;44(2):512-25
pubmed: 26050253
Nature. 2017 Oct 11;550(7675):204-213
pubmed: 29022597
Nat Genet. 2018 May;50(5):693-698
pubmed: 29686387
Genet Med. 2021 Jan;23(1):111-122
pubmed: 32855533
Am J Hum Genet. 2011 Jan 7;88(1):76-82
pubmed: 21167468
Am J Hum Genet. 2004 Apr;74(4):765-9
pubmed: 14997420
Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2222-30
pubmed: 16873731
Nat Genet. 2021 Jul;53(7):1097-1103
pubmed: 34017140
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Am J Hum Genet. 2016 Oct 6;99(4):877-885
pubmed: 27666373
J Med Genet. 2006 Mar;43(3):255-8
pubmed: 16085695
Nature. 2007 Oct 18;449(7164):851-61
pubmed: 17943122
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Nat Genet. 2018 Sep;50(9):1219-1224
pubmed: 30104762
Nat Genet. 2018 Apr;50(4):621-629
pubmed: 29632380
Nat Genet. 2018 Nov;50(11):1514-1523
pubmed: 30275531
Nat Commun. 2020 Jan 7;11(1):29
pubmed: 31911605
Circ Genom Precis Med. 2019 Jun;12(6):e002476
pubmed: 31211624
Circulation. 2020 Oct 27;142(17):1633-1646
pubmed: 32981348
Circulation. 2005 Feb 15;111(6):816-28
pubmed: 15710776
Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1248-58
pubmed: 17379839
Am J Hum Genet. 2021 Sep 2;108(9):1578-1589
pubmed: 34265237
FASEB J. 2005 Oct;19(12):1737-9
pubmed: 16099944

Auteurs

Derek Klarin (D)

Veterans Affairs (VA) Palo Alto Healthcare System, Palo Alto, CA, USA. dklarin@stanford.edu.
Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA. dklarin@stanford.edu.
ORCID: 0000-0002-4636-5780

Poornima Devineni (P)

Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.

Anoop K Sendamarai (AK)

Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.
Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-0476-5428

Anthony R Angueira (AR)

Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Sarah E Graham (SE)

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
ORCID: 0000-0003-1271-2489

Ying H Shen (YH)

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX, USA.

Michael G Levin (MG)

Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
ORCID: 0000-0002-9937-9932

James P Pirruccello (JP)

Division of Cardiology, University of California San Francisco, San Francisco, CA, USA.
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
ORCID: 0000-0001-6088-4037

Ida Surakka (I)

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.

Purushotham R Karnam (PR)

Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.

Tanmoy Roychowdhury (T)

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.

Yanming Li (Y)

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
ORCID: 0000-0002-8213-9166

Minxian Wang (M)

CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
ORCID: 0000-0002-3753-508X

Krishna G Aragam (KG)

Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0003-3223-9131

Kaavya Paruchuri (K)

Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0003-1228-1674

Verena Zuber (V)

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
UK Dementia Research Institute at Imperial College, Imperial College London, London, UK.
ORCID: 0000-0001-9827-1877

Gabrielle E Shakt (GE)

Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Noah L Tsao (NL)

Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0002-5743-0795

Renae L Judy (RL)

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

Ha My T Vy (HMT)

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Shefali S Verma (SS)

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0001-5216-4670

Daniel J Rader (DJ)

Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0002-9245-9876

Ron Do (R)

Icahn School of Medicine at Mount Sinai, New York, NY, USA.
ORCID: 0000-0002-3144-3627

Joseph E Bavaria (JE)

Division of Cardiovascular Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Girish N Nadkarni (GN)

Icahn School of Medicine at Mount Sinai, New York, NY, USA.
ORCID: 0000-0001-6319-4314

Marylyn D Ritchie (MD)

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
ORCID: 0000-0002-1208-1720

Stephen Burgess (S)

Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
ORCID: 0000-0001-5365-8760

Dong-Chuan Guo (DC)

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
ORCID: 0000-0002-7402-3104

Patrick T Ellinor (PT)

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-2067-0533

Scott A LeMaire (SA)

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
Department of Cardiovascular Surgery, Texas Heart Institute, Houston, TX, USA.
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
ORCID: 0000-0002-8736-4266

Dianna M Milewicz (DM)

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
ORCID: 0000-0002-7806-0068

Cristen J Willer (CJ)

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
ORCID: 0000-0001-5645-4966

Pradeep Natarajan (P)

Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0001-8402-7435

Philip S Tsao (PS)

Veterans Affairs (VA) Palo Alto Healthcare System, Palo Alto, CA, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Stanford Cardiovascular Institute, Stanford, CA, USA.
ORCID: 0000-0001-7274-9318

Saiju Pyarajan (S)

Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-9047-3762

Scott M Damrauer (SM)

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. scott.damrauer@pennmedicine.upenn.edu.
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA. scott.damrauer@pennmedicine.upenn.edu.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. scott.damrauer@pennmedicine.upenn.edu.
ORCID: 0000-0001-8009-1632

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genome-wide association study of thoracic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Genome-wide association study of thoracic...
questionsmedicales.fr › Personnes › Anciens combattants › Genome-wide association study of thoracic...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Pedigree › Genome-wide association study of thoracic...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Maladies de l'aorte › Anévrysme de l'aorte › Anévrysme de l'aorte thoracique › Genome-wide association study of thoracic...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Maladies de l'aorte › Syndrome aortique aigu › Dissection aortique › Genome-wide association study of thoracic...