Aortic disease has many forms including aortic aneurysm and dissection, aortic coarctation or abnormalities in aortic function, such as loss of aortic distensibility. Genetic analysis in humans is one of the most important experimental approaches in uncovering disease mechanisms, but the relative infrequency of thoracic aortic disease compared with other cardiovascular conditions such as coronary artery disease has hindered large-scale identification of genetic associations. In the past decade, advances in machine learning technology coupled with large imaging datasets from biobank repositories have facilitated a rapid expansion in our capacity to measure and genotype aortic traits, resulting in the identification of dozens of genetic associations. In this Review, we describe the history of technological advances in genetic discovery and explain how newer technologies such as deep learning can rapidly define aortic traits at scale. Furthermore, we integrate novel genetic observations provided by these advances into our current biological understanding of thoracic aortic disease and describe how these new findings can contribute to strategies to prevent and treat aortic disease.
Historically, familial studies provided the first footholds to understanding the genetic basis of aortic disease.
Approaches using machine learning to analyse millions of images within large datasets are accelerating the discovery of genetic loci associated with aortic disease phenotypes.
The genetic loci associated with aortic disease phenotypes highlight the importance of extracellular matrix and vascular smooth muscle cell function in the pathophysiology of aortic disease.
The highly heritable nature of aortic diameter, distensibility and strain raises the possibility that polygenic scores for quantitative aortic phenotypes will guide the identification of individuals at risk of sporadic aortopathy.
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Chou, E. L. & Lindsay, M. E. The genetics of aortopathies: hereditary thoracic aortic aneurysms and dissections. Am. J. Med. Genet. Part. C: Semin. Med. Genet. 184, 136–148 (2020).
Bossone, E. & Eagle, K. A. Epidemiology and management of aortic disease: aortic aneurysms and acute aortic syndromes. Nat. Rev. Cardiol. 18, 331–348 (2021).
Hiratzka, L. F. et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine. J. Am. Coll. Cardiol. 55, e27–e129 (2010).
Vilacosta, I. et al. Acute aortic syndrome revisited: JACC state-of-the-art review. J. Am. Coll. Cardiol. 78, 2106–2125 (2021).
Howard, D. P. et al. Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study. Circulation 127, 2031–2037 (2013).
Trimarchi, S. et al. Descending aortic diameter of 5.5 cm or greater is not an accurate predictor of acute type B aortic dissection. J. Thorac. Cardiovasc. Surg. 142, e101–e107 (2011).
Trimarchi, S. et al. Acute type B aortic dissection in the absence of aortic dilatation. J. Vasc. Surg. 56, 311–316 (2012).
Quintana, R. A. & Taylor, W. R. Cellular mechanisms of aortic aneurysm formation. Circ. Res. 124, 607–618 (2019).
Erbel, R. et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur. Heart J. 35, 2873–2926 (2014).
Chen, S.-W. et al. Association of long-term use of antihypertensive medications with late outcomes among patients with aortic dissection. JAMA Netw. Open. 4, e210469 (2021).
Salata, K. et al. Renin-angiotensin system blockade does not attenuate abdominal aortic aneurysm growth, rupture rate, or perioperative mortality after elective repair. J. Vasc. Surg. 67, 629–636.e2 (2018).
Pinard, A., Jones, G. T. & Milewicz, D. M. Genetics of thoracic and abdominal aortic diseases. Circ. Res. 124, 588–606 (2019).
Shan, Y. et al. Aortic stenosis exacerbates flow aberrations related to the bicuspid aortic valve fusion pattern and the aortopathy phenotype. Eur. J. Cardiothorac. Surg. 55, 534–542 (2019).
Mai, C. T. et al. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 111, 1420–1435 (2019).
Brown, M. L. et al. Coarctation of the aorta: lifelong surveillance is mandatory following surgical repair. J. Am. Coll. Cardiol. 62, 1020–1025 (2013).
Choudhary, P. et al. Late outcomes in adults with coarctation of the aorta. Heart 101, 1190–1195 (2015).
Hesslein, P. S., Gutgesell, H. P. & McNamara, D. G. Prognosis of symptomatic coarctation of the aorta in infancy. Am. J. Cardiol. 51, 299–303 (1983).
Bjornsson, T. et al. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. Eur. Heart J. 39, 3243–3249 (2018).
Ewart, A. K. et al. A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. Proc. Natl Acad. Sci. USA 90, 3226–3230 (1993).
Morris, C. A., Loker, J., Ensing, G. & Stock, A. D. Supravalvular aortic stenosis cosegregates with a familial 6;7 translocation which disrupts the elastin gene. Am. J. Med. Genet. 46, 737–744 (1993).
Redheuil, A. et al. Proximal aortic distensibility is an independent predictor of all-cause mortality and incident CV events: the MESA study. J. Am. Coll. Cardiol. 64, 2619–2629 (2014).
Resnick, L. M. et al. Direct magnetic resonance determination of aortic distensibility in essential hypertension: relation to age, abdominal visceral fat, and in situ intracellular free magnesium. Hypertension 30, 654–659 (1997).
Stefanadis, C., Wooley, C. F., Bush, C. A., Kolibash, A. J. & Boudoulas, H. Aortic distensibility abnormalities in coronary artery disease. Am. J. Cardiol. 59, 1300–1304 (1987).
Adams, J. N. et al. Aortic distensibility and stiffness index measured by magnetic resonance imaging in patients with Marfan’s syndrome. Br. Heart J. 73, 265–269 (1995).
Groenink, M., de Roos, A., Mulder, B. J., Spaan, J. A. & van der Wall, E. E. Changes in aortic distensibility and pulse wave velocity assessed with magnetic resonance imaging following beta-blocker therapy in the Marfan syndrome. Am. J. Cardiol. 82, 203–208 (1998).
Jeremy, R. W. et al. Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. Am. J. Cardiol. 74, 369–373 (1994).
Ohtsuka, S., Kakihana, M., Watanabe, H. & Sugishita, Y. Chronically decreased aortic distensibility causes deterioration of coronary perfusion during increased left ventricular contraction. J. Am. Coll. Cardiol. 24, 1406–1414 (1994).
Loeys, B. et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum. Mol. Genet. 11, 2113–2118 (2002).
Renard, M. et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J. Am. Coll. Cardiol. 72, 605–615 (2018).
Musunuru, K. et al. Genetic testing for inherited cardiovascular diseases: a scientific statement from the American Heart Association. Circ. Genom. Precis. Med. 13, e000067 (2020).
Pope, F. M. et al. Patients with Ehlers–Danlos syndrome type IV lack type III collagen. Proc. Natl Acad. Sci. USA 72, 1314–1316 (1975).
Tsipouras, P. et al. Ehlers–Danlos syndrome type IV: cosegregation of the phenotype to a COL3A1 allele of type III procollagen. Hum. Genet. 74, 41–46 (1986).
Superti-Furga, A., Gugler, E., Gitzelmann, R. & Steinmann, B. Ehlers–Danlos syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen. J. Biol. Chem. 263, 6226–6232 (1988).
Kainulainen, K., Pulkkinen, L., Savolainen, A., Kaitila, I. & Peltonen, L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N. Engl. J. Med. 323, 935–939 (1990).
Dietz, H. C. et al. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics 9, 355–361 (1991).
Godfrey, M. et al. Cosegregation of elastin-associated microfibrillar abnormalities with the Marfan phenotype in families. Am. J. Hum. Genet. 46, 652–660 (1990).
Hollister, D. W., Godfrey, M., Sakai, L. Y. & Pyeritz, R. E. Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N. Engl. J. Med. 323, 152–159 (1990).
Dietz, H. C. et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991).
Judge, D. P. et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Investig. 114, 172–181 (2004).
Pereira, L. et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat. Genet. 17, 218–222 (1997).
Loeys, B. L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet. 37, 275–281 (2005).
Micale, L. et al. Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis. Eur. J. Hum. Genet. 18, 317–323 (2010).
Faury, G. et al. Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J. Clin. Investig. 112, 1419–1428 (2003).
Guo, D. C. et al. Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat. Genet. 39, 1488–1493 (2007).
van de Laar, I. M. et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet. 43, 121–126 (2011).
Zhu, L. et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat. Genet. 38, 343–349 (2006).
Wang, L. et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am. J. Hum. Genet. 87, 701–707 (2010).
Wolford, B. N. et al. Clinical implications of identifying pathogenic variants in individuals with thoracic aortic dissection. Circ. Genom. Precis. Med. 12, e002476 (2019).
Milewicz, D. M., Regalado, E. S., Shendure, J., Nickerson, D. A. & Guo, D. C. Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc. Med. 24, 53–60 (2014).
Boileau, C. et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet. 44, 916–921 (2012).
Guo, D. C. et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am. J. Hum. Genet. 93, 398–404 (2013).
Guo, D. C. et al. LOX mutations predispose to thoracic aortic aneurysms and dissections. Circ. Res. 118, 928–934 (2016).
Lee, V. S. et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc. Natl Acad. Sci. USA 113, 8759–8764 (2016).
Lindsay, M. E. et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet. 44, 922–927 (2012).
Guo, D. C. et al. Genetic variants in LRP1 and ULK4 are associated with acute aortic dissections. Am. J. Hum. Genet. 99, 762–769 (2016).
LeMaire, S. A. et al. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat. Genet. 43, 996–1000 (2011).
Prakash, S. et al. Recurrent rare genomic copy number variants and bicuspid aortic valve are enriched in early onset thoracic aortic aneurysms and dissections. PLoS ONE 11, e0153543 (2016).
Vasan, R. S. et al. Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. JAMA 302, 168–178 (2009).
Wild, P. S. et al. Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. J. Clin. Investig. 127, 1798–1812 (2017).
Sudlow, C. et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
Goodfellow, I., Bengio, Y. & Courville, A. Deep Learning (MIT, 2016).
Pirruccello, J. P. et al. Deep learning enables genetic analysis of the human thoracic aorta. Nat. Genet. 54, 40–51 (2022).
Ronneberger O., Fischer P. & Brox T. In Medical Image Computing and Computer-Assisted Intervention – MICCAI 2015 (eds Navab, N., Hornegger, J., Wells, W. & Frangi, A.) 234–241 (Springer, 2015).
Krizhevsky, A., Sutskever, I. & Hinton, G. E. ImageNet classification with deep convolutional neural networks. Adv. Neural Inf. Process. Syst. 25, 1097–1105 (2012).
Bebis, G. et al. (eds) Advances in Visual Computing. 10th International Symposium, ISVC 2014, Proceedings, Part I (Springer, 2014).
Rosenfeld, A. & Pfaltz, J. L. Sequential operations in digital picture processing. J. ACM 13, 471–494 (1966).
Horn, B. K. P. Robot Vision. (MIT, 1986).
Tcheandjieu, C. et al. High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease. Nat. Genet. 54, 772–782 (2022).
Francis, C. M. et al. Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities. Nat. Commun. 13, 4505 (2022).
Nekoui, M. et al. Spatially distinct genetic determinants of aortic dimensions influence risks of aneurysm and stenosis. J. Am. Coll. Cardiol. 80, 486-497 (2022).
Lino Cardenas, C. L. et al. An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nat. Commun. 9, 1009 (2018).
Klarin, D. et al. Genetic architecture of abdominal aortic aneurysm in the Million Veteran Program. Circulation 142, 1633–1646 (2020).
MacFarlane, E. G. et al. Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys–Dietz syndrome. J. Clin. Investig. 129, 659–675 (2019).
Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016).
Malhotra, R. et al. HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype. Nat. Genet. 51, 1580–1587 (2019).
Davis, F. M. et al. Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms. J. Exp. Med. 218, e20201839 (2021).
Watanabe, K. et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 51, 1339–1348 (2019).
Spadaccio, C. et al. Old myths, new concerns: the long-term effects of ascending aorta replacement with Dacron grafts. not all that glitters is gold. J. Cardiovasc. Transl. Res. 9, 334–342 (2016).
Xu, J. & Shi, G.-P. Vascular wall extracellular matrix proteins and vascular diseases. Biochim. Biophys. Acta 1842, 2106–2119 (2014).
Szabo, Z. et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J. Med. Genet. 43, 255–258 (2006).
Hirai, M. et al. Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J. Cell Biol. 176, 1061–1071 (2007).
Papke, C. L. & Yanagisawa, H. Fibulin-4 and fibulin-5 in elastogenesis and beyond: insights from mouse and human studies. Matrix Biol. 37, 142–149 (2014).
Yanagisawa, H. et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415, 168–171 (2002).
Nakamura, T. et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415, 171–175 (2002).
Falak, S. et al. Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the rat. Physiol. Genom. 46, 418–428 (2014).
Rippe, C. et al. Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway. Sci. Rep. 7, 1334 (2017).
Evanko, S. P., Angello, J. C. & Wight, T. N. Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 19, 1004–1013 (1999).
Mohamed, R. et al. Transforming growth factor-β1 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells. J. Cell Commun. Signal. 13, 225–233 (2019).
Humphrey, J. D., Schwartz, M. A., Tellides, G. & Milewicz, D. M. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ. Res. 116, 1448–1461 (2015).
Yamashiro, Y. et al. Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. Sci. Signal. 8, ra105 (2015).
Tan, K. L. et al. Ari-1 regulates myonuclear organization together with parkin and is associated with aortic aneurysms. Dev. Cell 45, 226–244.e8 (2018).
Prager-Khoutorsky, M. et al. Fibroblast polarization is a matrix-rigidity-dependent process controlled by focal adhesion mechanosensing. Nat. Cell Biol. 13, 1457–1465 (2011).
Thomas, D. G. & Robinson, D. N. The fifth sense: mechanosensory regulation of alpha-actinin-4 and its relevance for cancer metastasis. Semin. Cell Dev. Biol. 71, 68–74 (2017).
Han, B. et al. Conversion of mechanical force into biochemical signaling. J. Biol. Chem. 279, 54793–54801 (2004).
Huelsmann, S., Rintanen, N., Sethi, R., Brown, N. H. & Ylanne, J. Evidence for the mechanosensor function of filamin in tissue development. Sci. Rep. 6, 32798 (2016).
Fujiwara, S., Matsui, T. S., Ohashi, K., Mizuno, K. & Deguchi, S. Keratin-binding ability of the N-terminal Solo domain of Solo is critical for its function in cellular mechanotransduction. Genes. Cell 24, 390–402 (2019).
Kurogane, Y. et al. FGD5 mediates proangiogenic action of vascular endothelial growth factor in human vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 32, 988–996 (2012).
Li, Y. et al. Variants of focal adhesion scaffold genes cause thoracic aortic aneurysm. Circ. Res. 128, 8–23 (2021).
Wu, J., Lewis, A. H. & Grandl, J. Touch, tension, and transduction – the function and regulation of piezo ion channels. Trends Biochem. Sci. 42, 57–71 (2017).
Huang, Y. Cardiovascular consequences of KATP overactivity in Cantu syndrome. JCI Insight 3, e121153 (2018).
Parrott, A. et al. Cantu syndrome: a longitudinal review of vascular findings in three individuals. Am. J. Med. Genet. A 182, 1243–1248 (2020).
Taviaux, S., Williams, M. E., Harpold, M. M., Nargeot, J. & Lory, P. Assignment of human genes for β2 and β4 subunits of voltage-dependent Ca2+ channels to chromosomes 10p12 and 2q22-q23. Hum. Genet. 100, 151–154 (1997).
Massett, M. P. et al. Loss of smooth muscle α-actin effects on mechanosensing and cell-matrix adhesions. Exp. Biol. Med. 245, 374–384 (2020).
Nair, R. R., Solway, J. & Boyd, D. D. Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression. J. Biol. Chem. 281, 26424–26436 (2006).
Jimenez, M., Daret, D., Choussat, A. & Bonnet, J. Immunohistological and ultrastructural analysis of the intimal thickening in coarctation of human aorta. Cardiovasc. Res. 41, 737–745 (1999).
Bertoli-Avella, A. M. et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J. Am. Coll. Cardiol. 65, 1324–1336 (2015).
Cannaerts, E. et al. Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype. J. Med. Genet. 56, 220–227 (2019).
Teekakirikul, P. et al. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. Am. J. Med. Genet. A 161A, 185–191 (2013).
Heald, B. et al. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome–hereditary hemorrhagic telangiectasia due to SMAD4. Am. J. Med. Genet. A 167A, 1758–1762 (2015).
Duan, X. Y. et al. SMAD4 rare variants in individuals and families with thoracic aortic aneurysms and dissections. Eur. J. Hum. Genet. 27, 1054–1060 (2019).
Lin, A. E. et al. Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome. Am. J. Med. Genet. A 170, 2617–2631 (2016).
Cook, J. R. et al. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler. Thromb. Vasc. Biol. 35, 911–917 (2015).
Zhao, Y., Hasse, S., Zhao, C. & Bourgoin, S. G. Targeting the autotaxin – lysophosphatidic acid receptor axis in cardiovascular diseases. Biochem. Pharmacol. 164, 74–81 (2019).
Watanabe, M. et al. Regulation of smooth muscle cell differentiation by AT-rich interaction domain transcription factors Mrf2α and Mrf2β. Circ. Res. 91, 382–389 (2002).
Li, N. et al. Mutations in the histone modifier PRDM6 are associated with isolated nonsyndromic patent ductus arteriosus. Am. J. Hum. Genet. 98, 1082–1091 (2016).
Luyckx, I. et al. Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene. Eur. J. Hum. Genet. 27, 1033–1043 (2019).
Aragam, K. G. & Natarajan, P. Polygenic scores to assess atherosclerotic cardiovascular disease risk: clinical perspectives and basic implications. Circ. Res. 126, 1159–1177 (2020).
Adeyemo, A. et al. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps. Nat. Med. 27, 1876–1884 (2021).
Ntalla, I. et al. genetic risk score for coronary disease identifies predispositions to cardiovascular and noncardiovascular diseases. J. Am. Coll. Cardiol. 73, 2932–2942 (2019).
Pirruccello, J. P. et al. Deep learning enables genetic analysis of the human thoracic aorta. Nat. Genet. 54, 40–51 (2022).
Li, Y. et al. Single-cell transcriptome analysis reveals dynamic cell populations and differential gene expression patterns in control and aneurysmal human aortic tissue. Circulation 142, 1374–1388 (2020).
Pedroza, A. J. et al. Single-cell transcriptomic profiling of vascular smooth muscle cell phenotype modulation in Marfan syndrome aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 40, 2195–2211 (2020).
van’t Hoff, F. N. G. et al. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms. J. Am. Heart Assoc. 5, e002603 (2016).
E.C. is supported by the National Institutes of Health (T32HL007208) and the Vascular and Endovascular Surgery Society Resident Research Award. J.P.P. is supported by the National Institutes of Health (K08HL159346) and a Sarnoff Cardiovascular Research Foundation Scholar Award. P.T.E. is supported by the Fondation Leducq (14CVD01), the National Institutes of Health (1RO1HL092577, K24HL105780) and the AHA (18SFRN34110082). M.E.L. is supported by the National Institutes of Health (1RO1HL130113) and the Toomey Fund for Aortic Research.
J.P.P. has consulted for Maze Therapeutics. P.T.E. receives sponsored research support from Bayer AG and IBM Health, and has served on advisory boards or as a consulted for Bayer AG, MyoKardia, Novartis and Quest Diagnostics. M.E.L. has received support from Bayer AG. E.C. declares no competing interests.
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Chou, E., Pirruccello, J.P., Ellinor, P.T. et al. Genetics and mechanisms of thoracic aortic disease. Nat Rev Cardiol (2022). https://doi.org/10.1038/s41569-022-00763-0