ArticleNature communications2017
Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.
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Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 2 of them syntheses that pooled it.
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65citing papers in PubMed, 2 pooled it
5.7field-weighted citation impact, top 3% of its field
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Who cites it
65 citing papers in PubMed, 2 syntheses or guidelines pooled it, 126 citations in OpenAlex.
- Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve.Circulation · 2026Pooled it
- What is the Impact of Endothelial-to-Mesenchymal Transition in Solid Tumours: A Qualitative Systematic Review and Quantitative Meta-Analysis.International journal of biological sciences · 2025Pooled it
- Rare type I collagen variants in early-onset bicuspid aortic valve disease: Overlap with Ehlers-Danlos syndrome and osteogenesis imperfecta.HGG advances · 2026Article
- A cell atlas of the developing human outflow tract of the heart and its adult aortic valve derivatives.eLife · 2026Article
- Rare regulatory mutations disrupt mesenchymal molecular programs driving endocardial cushion formation in bicuspid aortic valve.Nature communications · 2026Article
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Transformative Potential of Induced Pluripotent Stem Cells in Congenital Heart Disease Research and Treatment.Children (Basel, Switzerland) · 2025Review
- Age Differences in Aortic Stenosis.Reviews in cardiovascular medicine · 2025Review
- Chromosomal Location and Identification ofDiagnostics (Basel, Switzerland) · 2025Article
- 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.Circulation · 2025Review
- Calcific aortic stenosis: omics-based target discovery and therapy development.European heart journal · 2025Review
- Current advances in human-induced pluripotent stem cell-based models and therapeutic approaches for congenital heart disease.Molecular and cellular biochemistry · 2025Review
- Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys-Dietz syndrome mouse model.Nature cardiovascular research · 2024Article
- Insights into the Inherited Basis of Valvular Heart Disease.Current cardiology reports · 2024Review
- Observational
- 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.Circulation · 2024Review
- Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.Advances in experimental medicine and biology · 2024Article
- Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.Pediatric research · 2024Article
- Lineage Tracing Identifies Dynamic Contribution of Endothelial Cells to Cardiac Valve Mesenchyme During Development.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2023Article
- Spatial transcriptomics reveals novel genes during the remodelling of the embryonic human arterial valves.PLoS genetics · 2023Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
44 authors at 9 institutions in 6 countries.
Bo YangDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Wei ZhouDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jiao JiaoDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jonas B NielsenDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.ORCID 0000-0002-6654-2852
Michael R MathisDepartment of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mahyar HeydarpourDepartment of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Guillaume LettreMontreal Heart Institute, Montreal, Quebec, Canada HIT 1C8.
Lasse FolkersenCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
Siddharth PrakashDepartment of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.
Claudia SchurmannThe Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Lars FritscheDepartment of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.ORCID 0000-0002-2110-1690
Gregory A FarnumDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.ORCID 0000-0002-0192-8252
Maoxuan LinDivision of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mohammad OthmanDepartment of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA.
Whitney HornsbyFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Anisa DriscollFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Alexandra LevasseurFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Marc ThomasFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Linda FarhatFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Marie-Pierre DubéMontreal Heart Institute, Montreal, Quebec, Canada HIT 1C8.
Eric M IsselbacherDepartment of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Anders Franco-CerecedaCardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
Dong-Chuan GuoDepartment of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.
Erwin P BottingerThe Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
G Michael DeebDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Anna BooherFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Sachin KheterpalDepartment of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Y Eugene ChenDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA.
Hyun Min KangDepartment of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jacob KitzmanDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Heather J CordellInstitute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK.
Bernard D KeavneyDivision of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.
Judith A GoodshipInstitute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne NE1 3BZ, UK.
Santhi K GaneshFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Gonçalo AbecasisDepartment of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Kim A EagleFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Alan P BoyleDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.ORCID 0000-0002-2081-1105
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Per ErikssonCardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm SE-171 76, Sweden.
Jean-Claude TardifMontreal Heart Institute, Montreal, Quebec, Canada HIT 1C8.
Chad M BrummettDepartment of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Dianna M MilewiczDepartment of Internal Medicine, Division of Medical Genetics, University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.
Simon C BodyDepartment of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cristen J WillerFrankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan 48109, USA.ORCID 0000-0001-5645-4966
University of Michigan · USBrigham and Women's Hospital · USChild Health and Development Institute · USKarolinska University Hospital · SEMontreal Heart Institute · CAThe University of Texas Health Science Center · USNewcastle University · GBNorwegian University of Science and Technology · NOUniversity of Manchester · GB
Funding
Center for Clinical and Translational Sciences (CCTS)UL1TR000371 · NCATS · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI MCPHERSON, DAVID D · 2012 to 2016
$13.4MUsing genetics to discover mechanisms of myocardial infarctionR01HL109946 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI YUQING Eugene CHEN, Ida Liisa Surakka · 2011 to 2026
$8.9MUsing genetic variation to study biology of blood lipids & coronary heart diseaseR01HL127564 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Pradeep Natarajan, Gina Marie Peloso · 2015 to 2026
$7.3MUsing Genetics to Inform Mechanism of Cardiovascular DiseaseR35HL135824 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI WILLER, CRISTEN J · 2017 to 2022
$5.4MLIMBIC &MEDULLARY MECH. IN COCAINE-RELATED SUDDEN DEATHR01DA006227 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI MASH, DEBORAH C. · 1990 to 2012
$3.7MEpigenetic Marks of Cocaine AddictionR01DA033684 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI MASH, DEBORAH C., TURECKI, GUSTAVO · 2011 to 2015
$3.6MDiverse ancestry biobank to map biomedical traits and elucidate health disparitieU01HG007417 · NHGRI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI LOOS, RUTH JF · 2013 to 2017
$3.5MGenetic Studies of The Impact of Hematologic Traits On Cardiovascular DiseaseR01HL122684 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GANESH, SANTHI K · 2015 to 2019
$3.4MMethods for high-resolution analysis of genetic effects on gene expressionR01MH101814 · NIMH · UNIVERSITY OF GENEVA · PI BUSTAMANTE, CARLOS DANIEL, DERMITZAKIS, EMMANOUIL · 2013 to 2016
$2.3MHarnessing GTEx to Create Transcriptome Knowledge and Inform Disease BiologyR01MH101820 · NIMH · UNIVERSITY OF CHICAGO · PI COX, NANCY J, NICOLAE, DAN LIVIU · 2013 to 2015
$2.3MResource Informatics and ProductionU41HG009293 · NHGRI · STANFORD UNIVERSITY · PI BOYLE, ALAN P · 2017 to 2019
$2.2MGenetic Etiology of Bicuspid Aortic Valve DiseaseR01HL114823 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI BODY, SIMON C · 2012 to 2016
$2.1MBritish Heart Foundation RG/15/12/31616CCR NIH HHS HHSN261200800001CNCATS NIH HHS UL1 TR000371NCI NIH HHS HHSN261200800001ENHGRI NIH HHS U01 HG007417NHGRI NIH HHS U41 HG009293NHLBI NIH HHS HHSN268201000029CNHLBI NIH HHS K08 HL130614NHLBI NIH HHS R01 HL109946NHLBI NIH HHS R01 HL114823NHLBI NIH HHS R01 HL122684NHLBI NIH HHS R01 HL127564NHLBI NIH HHS R01 HL130705NHLBI NIH HHS R35 HL135824NIDA NIH HHS R01 DA006227NIDA NIH HHS R01 DA033684NIH HHS S10 OD018522NIMH NIH HHS R01 MH090936NIMH NIH HHS R01 MH090937NIMH NIH HHS R01 MH090941NIMH NIH HHS R01 MH090948NIMH NIH HHS R01 MH090951NIMH NIH HHS R01 MH101782NIMH NIH HHS R01 MH101810NIMH NIH HHS R01 MH101814NIMH NIH HHS R01 MH101819NIMH NIH HHS R01 MH101820NIMH NIH HHS R01 MH101822NIMH NIH HHS R01 MH101825
Abstract
Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.
Indexed as
Genetic VariationAmino Acid SubstitutionAortic ValveBicuspid Aortic Valve DiseaseCase-Control StudiesCell TransdifferentiationCRISPR-Cas SystemsFemaleGATA4 Transcription FactorGene Regulatory NetworksGenome-Wide Association StudyHeart Defects, CongenitalHeart Valve DiseasesHumansInduced Pluripotent Stem CellsMaleGATA4 protein, humanGATA4 Transcription FactorRNA, Untranslated
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