Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm

Tanmoy Roychowdhury; Haocheng Lu; Whitney E Hornsby; Bradley Crone; Gao T Wang; Dong-Chuan Guo; Anoop K Sendamarai; Poornima Devineni; Maoxuan Lin; Wei Zhou; Sarah E Graham; Brooke N Wolford; Ida Surakka; Zhenguo Wang; Lin Chang; Jifeng Zhang; Michael Mathis; Chad M Brummett; Tori L Melendez; Michael J Shea; Karen Meekyong Kim; G Michael Deeb; Himanshu J Patel; Jonathan Eliason; Kim A Eagle; Bo Yang; Santhi K Ganesh; Ben Brumpton; Bjørn Olav Åsvold; Anne Heidi Skogholt; Kristian Hveem; VA Million Veteran Program; Saiju Pyarajan; Derek Klarin; Philip S Tsao; Scott M Damrauer; Suzanne M Leal; Dianna M Milewicz; Y Eugene Chen; Minerva T Garcia-Barrio; Cristen J Willer

doi:10.1016/j.ajhg.2021.06.016

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm

Am J Hum Genet. 2021 Sep 2;108(9):1578-1589. doi: 10.1016/j.ajhg.2021.06.016. Epub 2021 Jul 14.

Authors

Tanmoy Roychowdhury¹, Haocheng Lu¹, Whitney E Hornsby¹, Bradley Crone², Gao T Wang³, Dong-Chuan Guo⁴, Anoop K Sendamarai⁵, Poornima Devineni⁶, Maoxuan Lin⁷, Wei Zhou⁸, Sarah E Graham¹, Brooke N Wolford², Ida Surakka¹, Zhenguo Wang¹, Lin Chang¹, Jifeng Zhang¹, Michael Mathis⁹, Chad M Brummett¹⁰, Tori L Melendez¹, Michael J Shea¹, Karen Meekyong Kim¹¹, G Michael Deeb¹¹, Himanshu J Patel¹¹, Jonathan Eliason¹², Kim A Eagle¹, Bo Yang¹¹, Santhi K Ganesh¹³, Ben Brumpton¹⁴, Bjørn Olav Åsvold¹⁵, Anne Heidi Skogholt¹⁶, Kristian Hveem¹⁷; VA Million Veteran Program; Saiju Pyarajan¹⁸, Derek Klarin¹⁹, Philip S Tsao²⁰, Scott M Damrauer²¹, Suzanne M Leal²², Dianna M Milewicz⁴, Y Eugene Chen²³, Minerva T Garcia-Barrio²⁴, Cristen J Willer²⁵

Affiliations

¹ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
³ Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
⁴ Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 70030, USA.
⁵ Center 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.
⁶ Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA.
⁷ Department 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.
⁸ Department 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.
⁹ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁰ Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
¹² Department of Surgery, Section of Vascular Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
¹³ Department 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.
¹⁴ K.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.
¹⁵ K.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.
¹⁶ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.
¹⁷ K.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.
¹⁸ Center for Data and Computational Sciences, VA Boston Healthcare System, Boston, MA 02130, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹⁹ Malcolm 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.
²⁰ VA Palo Alto Health Care System, Palo Alto, CA 94304, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305-5406, USA.
²¹ Department 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.
²² Center 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.
²³ Department 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.
²⁴ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
²⁵ Department 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: [email protected].

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.

Keywords: GWAS; TCF7L2; VSMC; apoptosis; regulatory variant; thoracic aortic aneurysm.

Publication types

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

MeSH terms

Aorta / metabolism
Aorta / pathology
Aortic Aneurysm, Thoracic / genetics*
Aortic Aneurysm, Thoracic / metabolism
Aortic Aneurysm, Thoracic / pathology
Case-Control Studies
Caspase 3 / genetics
Caspase 3 / metabolism
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / pathology
Endothelial Cells / metabolism*
Endothelial Cells / pathology
Gene Expression Regulation
Genome, Human
Genome-Wide Association Study
Humans
Introns
Michigan
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Mutation
Proto-Oncogene Proteins c-bcl-2 / genetics*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Quantitative Trait Loci*
Transcription Factor 7-Like 2 Protein / genetics*
Transcription Factor 7-Like 2 Protein / metabolism
bcl-2-Associated X Protein / genetics
bcl-2-Associated X Protein / metabolism

Substances

BAX protein, human
BCL2 protein, human
Proto-Oncogene Proteins c-bcl-2
TCF7L2 protein, human
Transcription Factor 7-Like 2 Protein
bcl-2-Associated X Protein
CASP3 protein, human
Caspase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding