ArticleAmerican journal of human genetics2021
Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 3 of them syntheses that pooled it.
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27citing papers in PubMed, 3 pooled it
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Who cites it
27 citing papers in PubMed, 3 syntheses or guidelines pooled it, 56 citations in OpenAlex.
- Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve.Circulation · 2026Pooled it
- Integrative Genome-wide Association Meta-analysis of Aortic Aneurysm and Dissection Identifies Five Novel Genes.Genomics, proteomics & bioinformatics · 2025Pooled it
- Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.Nature genetics · 2023Pooled it
- TCF7L2 promotes abdominal aortic aneurysm through smooth muscle cell-mediated extracellular matrix remodeling.JCI insight · 2026Article
- Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.Frontiers in nutrition · 2026Article
- Mendelian Randomization Suggests a Causal Link Between Glycemic Traits and Thoracic Aortic Structures and Diseases.JACC. Basic to translational science · 2025Article
- Association of air pollution exposure and genetic susceptibility with increased risk of thoracic aortic aneurysm and dissection.Nature cardiovascular research · 2025Article
- A genetic map of human metabolism across the allele frequency spectrum.Nature genetics · 2025Article
- Causal associations between 17 common autoimmune diseases and aortic diseases: a Mendelian randomization study.International journal of cardiology. Cardiovascular risk and prevention · 2025Article
- Mitochondrial NADNature cardiovascular research · 2025Article
- Human Genetic Evidence to Inform Clinical Development of IL-6 Signaling Inhibition for Abdominal Aortic Aneurysm.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Systematic Mendelian Randomization Exploring Druggable Genes for Hemorrhagic Strokes.Molecular neurobiology · 2025Article
- Distinct Patterns of Smooth Muscle Phenotypic Modulation in Thoracic and Abdominal Aortic Aneurysms.Journal of cardiovascular development and disease · 2024Article
- Abdominal aortic aneurysm and cardiometabolic traits share strong genetic susceptibility to lipid metabolism and inflammation.Nature communications · 2024Article
- Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections.Basic research in cardiology · 2024Review
- Sleep Pattern, Genetic Susceptibility, and Abdominal Aortic Aneurysm in UK Biobank Participants: Large-Scale Cohort Study.JACC. Advances · 2024Article
- Article
- The causal relationship between thoracic aortic aneurysm and immune cells: a mendelian randomization study.BMC cardiovascular disorders · 2024Article
- Sex-specific genetic architecture of blood pressure.Nature medicine · 2024Article
- Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
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Authors and funding
41 authors at 11 institutions in 2 countries.
Tanmoy RoychowdhuryDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Haocheng LuDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Whitney E HornsbyDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Bradley CroneDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Gao T WangCenter for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Dong-Chuan GuoDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.
Anoop K SendamaraiCenter for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA; Booz Allen Hamilton, McLean, VA 22102, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Poornima DevineniCenter for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA.
Maoxuan LinDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA 02114, USA.
Wei ZhouDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Sarah E GrahamDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Brooke N WolfordDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Ida SurakkaDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Zhenguo WangDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Lin ChangDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Jifeng ZhangDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Michael MathisDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
Chad M BrummettDepartment of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
Tori L MelendezDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Michael J SheaDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Karen Meekyong KimDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
G Michael DeebDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Himanshu J PatelDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Jonathan EliasonDepartment of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Kim A EagleDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Bo YangDepartment of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Santhi K GaneshDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Ben BrumptonK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway; Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7030, Norway; HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger 7600, Norway.
Bjørn Olav ÅsvoldK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway; HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger 7600, Norway; Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7030, Norway.
Anne Heidi SkogholtK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.
Kristian HveemK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway; HUNT Research Center, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger 7600, Norway.
VA Million Veteran Program
Saiju PyarajanCenter for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Derek KlarinMalcolm Randall VA Medical Center, Gainesville, FL 32608, USA; Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32608, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Philip S TsaoVA Palo Alto Health Care System, Palo Alto, CA 94304, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5406, USA.
Scott M DamrauerDepartment of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Suzanne M LealCenter for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Alzheimer disease and the Aging Brain, Columbia University, NY 10032, USA.
Dianna M MilewiczDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.
Y Eugene ChenDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Minerva T Garcia-BarrioDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: minerva@med.umich.edu.
Cristen J WillerDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: cristen@umich.edu.
University of Michigan–Ann Arbor · USNorwegian University of Science and Technology · NOThe University of Texas Health Science Center at Houston · USVA Boston Healthcare System · USBooz Allen Hamilton (United States) · USColumbia University · USColumbia University Irving Medical Center · USMalcom Randall VA Medical Center · USStanford University · USSt Olav's University Hospital · NOUniversity of Pennsylvania · US
Funding
Regional Pilot And Feasibility Study Grants ProgramP30DK020572 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Scott Soleimanpour · 2013 to 2026
$24.3MUniversity of Michigan Training Program in Genomic ScienceT32HG000040 · NHGRI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Sebastian Zoellner · 1995 to 2026
$16.4MUsing genetics to discover mechanisms of myocardial infarctionR01HL109946 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI YUQING Eugene CHEN, Ida Liisa Surakka · 2011 to 2026
$8.9MGenetic Predisposition To Thoracic Aortic Aneurysms/DissectionsR01HL109942 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI MILEWICZ, DIANNA M · 2012 to 2023
$7.5MUsing Genetics to Inform Mechanism of Cardiovascular DiseaseR35HL135824 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI WILLER, CRISTEN J · 2017 to 2022
$5.4MKLF14 and Cardiovascular DiseaseR01HL134569 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHEN, YUQING EUGENE · 2017 to 2024
$5.3MTherapeutic Insights into Loeys-Dietz Syndrome using Humanized ModelsR01HL151776 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Bo Yang · 2020 to 2026
$4.2MDefine the mechanisms of aortopathy in bicuspid aortic valve patientsR01HL141891 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI YANG, BO · 2018 to 2022
$3.5MPartners Healthcare Training Program in Precision and Genomic MedicineT32HG010464 · NHGRI · MASSACHUSETTS GENERAL HOSPITAL · PI HEIDI L REHM, JORDAN W SMOLLER · 2019 to 2026
$3.1MIDOL and dyslipidemia in cardiovascular diseasesR01HL147527 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHEN, YUQING EUGENE · 2019 to 2022
$3.1MKruppel-like factor 11 (KLF11) and atherosclerosisR01HL138139 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ZHANG, JIFENG · 2017 to 2021
$2.3MThe Role of TM6SF2 in Cardiovascular DiseaseR01HL137214 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CHEN, YUQING EUGENE · 2017 to 2020
$2.2MBLRD VA I01 BX003362CSRD VA IK2 CX001780NHGRI NIH HHS T32 HG000040NHGRI NIH HHS T32 HG010464NHLBI NIH HHS K08 HL130614NHLBI NIH HHS R01 HL109942NHLBI NIH HHS R01 HL109946NHLBI NIH HHS R01 HL122664NHLBI NIH HHS R01 HL134569NHLBI NIH HHS R01 HL137214NHLBI NIH HHS R01 HL138139NHLBI NIH HHS R01 HL141891NHLBI NIH HHS R01 HL142023NHLBI NIH HHS R01 HL147527NHLBI NIH HHS R01 HL151776NHLBI NIH HHS R35 HL135824NIDDK NIH HHS P30 DK020572
Abstract
Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
Indexed as
Quantitative Trait LociAortaAortic Aneurysm, Thoracicbcl-2-Associated X ProteinCase-Control StudiesCaspase 3Diabetes Mellitus, Type 2Endothelial CellsGene Expression RegulationGenome, HumanGenome-Wide Association StudyHumansIntronsMichiganMuscle, Smooth, VascularMutationBAX protein, humanbcl-2-Associated X ProteinBCL2 protein, humanCASP3 protein, humanCaspase 3Proto-Oncogene Proteins c-bcl-2TCF7L2 protein, humanTranscription Factor 7-Like 2 ProteinapoptosisGWASregulatory variantTCF7L2thoracic aortic aneurysmVSMC
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