Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm

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

doi:10.1016/j.ajhg.2021.06.016

Cited by 23 publications

(25 citation statements)

References 83 publications

(85 reference statements)

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“…2 and 3). We replicated the known FBN1 3 , ULK4 4 , and LRP1 4 loci at genome-wide signi cance, and the recently identi ed TCF7L2 5 locus with P < 5x10 -5 (Supplementary Table 2). Notably, in MVP we found no evidence of association for 3 variants previously reported in an analysis of 435 thoracic aortic aneurysm cases that lacked independent replication 8 , suggesting these rare variant associations may be false positive ndings (Supplementary Table 3).…”

Section: Common Variants Associated With Taadsupporting

confidence: 64%

“…These identi ed genetic variants, generally missense or nonsense mutations, substantially alter a gene's protein product and subsequently disrupt critical functions in VSMC contraction, extracellular matrix stabilization, or TGFb signaling 6 . While prior GWAS have identi ed 4 TAAD risk loci [3][4][5] , given the relatively rare incidence of TAAD in the population it remained unclear whether common or rare variants were the primary driver of TAAD heritability. In the current study, we increase the number of TAAD risk loci by a factor of 5 and identify putative causal risk genes that likely affect disease through changes in gene expression akin to other common complex traits.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, dissections of the ascending (Stanford Type A) or descending thoracic (Stanford Type B) are lifethreatening condition requiring emergency treatment, often including surgical repair, and are associated with high short and long-term mortality risk 1,2 . Despite the lethality of these conditions, the genetic determinants of TAAD remain largely unknown, with published genome-wide associations studies (GWAS) having revealed only 4 loci reaching genome-wide signi cance [3][4][5] . As a result, most of what is understood about the genetics of TAAD has been derived from studies examining rare, pathogenic variants resulting in heritable aortopathy (so called, hereditary TAAD or "HTAAD") 6 .…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide Association Study of Thoracic Aortic Aneurysm and Dissection in the Million Veteran Program

Klarin

Devineni

Sendamarai

et al. 2022

Preprint

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Current understanding of the genetic contribution to thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies focusing on rare, Mendelian forms of disease. In the current analysis we performed the largest genome-wide association study (GWAS) of TAAD to date, testing ~25 million DNA sequence variants in 8,626 participants with (7,050 European, 1,266 African, and 310 Hispanic ancestry individuals) and 453,043 participants without TAAD in the Million Veteran Program. The results were replicated in an independent sample of 4,459 individuals with and 512,463 without TAAD from 6 cohorts. We identified 21 TAAD loci, 17 of which have not been previously reported. We leverage phenome-wide scanning and causal inference methods to provide evidence that TAAD is a non-atherosclerotic aortic disorder distinct form other forms of vascular disease; we subsequently use Bayesian techniques and single cell/nucleus RNA sequencing data to identify causal risk genes and cell types. Finally, we generate a TAAD polygenic risk score and demonstrate that those at the top 5% of polygenic risk are over 4-fold more likely to experience an incident, fatal TAAD event. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and is not solely inherited through protein altering variants of large effect size. These data provide new mechanistic insights into TAAD risk and improve our understanding of thoracic aortic disease.

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Section: Common Variants Associated With Taadsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genome-wide Association Study of Thoracic Aortic Aneurysm and Dissection in the Million Veteran Program

Klarin

Devineni

Sendamarai

et al. 2022

Preprint

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“…In contrast, differences in overlap with lipid metabolism genes likely indicate larger involvement of lipid levels as a risk factor for AAA compared to TAA. Consistent with this, previous studies reported a significant genetic correlation between lipids and AAA (Klarin et al ., 2020), but not TAA (Roychowdhury et al ., 2021).…”

Section: Resultsmentioning

confidence: 99%

“…While there is human genetics evidence regarding the role of TGF-β signaling pathway in thoracic aortic aneurysm (TAA) (Pinard et al, 2019), which is characterized by dilation of the aortic root or the ascending/descending aorta nearest the heart itself, this GWAS provides the human genetics evidence of the involvement of this pathway in AAA as well, and suggests shared biology between the two diseases. To further investigate the overlap between AAA and TAA genes, we queried the association of AAA index variants in a recent TAA GWAS (n=1,351) (Roychowdhury et al, 2021) and observed 24 AAA index variants associated with TAA at P<0.05. These variants are generally associated with AAA with weaker effect estimates compared to TAA ( Figure S8 ).…”

Section: Resultsmentioning

confidence: 99%

Multi-ancestry GWAS deciphers genetic architecture of abdominal aortic aneurysm and highlightsPCSK9as a therapeutic target

Roychowdhury

Klarin

Levin

et al. 2022

Preprint

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Abdominal aortic aneurysm (AAA) is a common disease with significant heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 144 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis was able to explain AAA beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in the pathogenesis of AAA. We further integrated functional data to elucidate expression of genes associated with AAA. These genes also indicate crossover between the development of AAA and other monogenic aortopathies, particularly via TGF-beta signaling pathways. Motivated by the strong evidence for the role of lipid levels in AAA by PheWAS, we identified therapeutic opportunities using Mendelian Randomization and, in pre-clinical studies, we demonstrated that PCSK9 inhibition in mice prevented the development of AAA.

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Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

Ganizada,

J. A. Veltrop,

Akbulut

et al. 2024

Basic Res Cardiol

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Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM–VSMC network.

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Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm

Cited by 23 publications

References 83 publications

Genome-wide Association Study of Thoracic Aortic Aneurysm and Dissection in the Million Veteran Program

Genome-wide Association Study of Thoracic Aortic Aneurysm and Dissection in the Million Veteran Program

Multi-ancestry GWAS deciphers genetic architecture of abdominal aortic aneurysm and highlightsPCSK9as a therapeutic target

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

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