High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

Tcheandjieu, Catherine; Xiao, Ke; Tejeda, Heliodoro; Lynch, Julie; Ruotsalainen, Sanni; Bellomo, Tiffany; Palnati, Madhuri; Judy, Renae; Klarin, Derek; Kember, Rachel L.; Verma, Shefali S.; Abecasis, Gonçalo R.; Baras, Aris; Cantor, Michael; Coppola, Giovanni; Deubler, Andrew; Economides, Aris; Karalis, Katia; Lotta, Luca A.; Overton, John D.; Reid, Jeffrey G.; Siminovitch, Katherine A.; Shuldiner, Alan R.; Beechert, Christina; Forsythe, Caitlin; Fuller, Erin D.; Gu, Zhenhua; Lattari, Michael; Lopez, Alexander; Padilla, Maria Sotiopoulos; Pradhan, Manasi; Manoochehri, Kia; Schleicher, Thomas D.; Widom, Louis; Wolf, Sarah; Ulloa, Ricardo H.; Averitt, Amelia J.; Banerjee, Nilanjana; Li, Dadong; Malhotra, Sameer; Sharma, Deepika; Staples, Jeffrey; Bai, Xiaodong; Balasubramanian, Suganthi; Bao, Suying; Boutkov, Boris; Chen, Siying; Eom, Gisu; Habegger, Lukas; Hawes, Alicia; Khalid, Shareef; Krasheninina, Olga; Lanche, Rouel; Mansfield, Adam; Maxwell, Evan K.; Mitra, George; Nafde, Mona; O’Keeffe, Sean; Orelus, Max; Panea, Razvan; Polanco, Tommy; Rasool, Ayesha; Salerno, William; Sun, Kathie; Xin, Jiwen; Backman, Joshua; Damask, Amy; Dobbyn, Lee; Ferreira, Manuel A. R.; Ghosh, Arkopravo; Gillies, Christopher E.; Gurski, Lauren; Jorgenson, Eric; Kang, Hyun Min; Kessler, Michael; Kosmicki, Jack A.; Li, Alexander; Lin, Nan; Liu, Daren; Locke, Adam E.; Marchini, Jonathan; Marcketta, Anthony; Mbatchou, Joelle; Moscati, Arden; Paulding, Charles; Sidore, Carlo; Stahl, Eli A.; Watanabe, Kyoko; Ye, Bin; Zhang, Blair; Ziyatdinov, Andrey; Jones, Marcus B.; Mighty, Jason; Mitnaul, Lyndon J.; Palotie, Aarno; Daly, Mark J.; Ritchie, Marylyn D.; Rader, Daniel J.; Rivas, Manuel A.; Assimes, Themistocles L.; Tsao, Philip S.; Damrauer, Scott M.; Priest, James R.

doi:10.1038/s41588-022-01070-7

Cited by 35 publications

(27 citation statements)

References 65 publications

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“…In agreement with previous studies, our measurements were significantly larger in men than women, 10,17,18 with increased aortic diameter in men suggested as a reason for the greater incidence of AAA in men. 19 We found that CSA IDPs increased with advancing age, in both men and women.…”

Section: Discussionsupporting

confidence: 93%

“…The strongest association was observed for the thoracic descending aorta, which is perhaps to be expected since this measurement closely corresponds to the location of CMR measurements of the ascending and descending aorta. 10 In agreement with previous studies, our measurements were significantly larger in men than women, 10,17,18 with increased aortic diameter in men suggested as a reason for the greater incidence of AAA in men. 19 We found that CSA IDPs increased with advancing age, in both men and women.…”

Section: Discussionsupporting

confidence: 92%

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Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Basty

Sorokin

Thanaj

et al. 2022

Preprint

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MRI measurements of heart volumes and vessel dimensions typically require specialised cardiac MRI examinations, which can be time consuming and resource intensive. Simpler scans covering the heart and major blood vessels of the abdomen may potentially provide useful clinical information. We used deep learning to segment cardiovascular structures from UK Biobank (UKBB) abdominal MRI scans and extracted six image-derived phenotypes (heart volume, and cross-sectional areas of the aorta and vena cava at key anatomical locations) from 44,541 participants. We found strong correlations between our measurements and those acquired using conventional cardiac MRI (CMR), with the strength of the association reflecting the degree of anatomical similarity between the measurements. We replicated previous findings related to gender differences and age-related changes in heart and vessel dimensions, and identified a significant association between infrarenal descending aorta cross-sectional area and incident aneurysm, and between heart volume and several cardiovascular disorders. In a genome-wide association study we identified 72 associations at 59 loci, of which 15 had not been previously associated with CMR IDPs. Furthermore, we demonstrated substantial genetic correlation with cardiovascular traits including varicose veins, aneurysms, dysrhythmia and cardiac failure. Our heritability enrichment implicated vascular tissue in the heritability of these traits. We derived a polygenic risk score for each trait and demonstrated an association with aneurysm diagnosis, pointing to a potential screening method for individuals at high-risk of this condition. Our work highlights the rich information content of abdominal MRI and the high degree of overlap with CMR.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Basty

Sorokin

Thanaj

et al. 2022

Preprint

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“…A common finding across these studies has been the observation that the genes and pathways identified by studying variation in cardiovascular traits among largely disease-free populations recapitulate known disease-associated genes and pathways. For example, recent GWAS of thoracic aorta diameters among healthy individuals implicate known Mendelian aortopathy genes like FBN1 70 , 71 , GWAS of electrocardiographic traits find long-QT syndrome-associated genes like SCN5A are associated with variation in many other subclinical electrocardiographic traits 72 , and GWAS of both left- and right-heart structure/function among healthy individuals identify Mendelian cardiomyopathy genes 23 , 73 , 74 . We demonstrate an example of linking GWAS of a common, complex trait like HF, with GWAS of detailed cardiac structure/function endophenotypes, and recapitulate known Mendelian cardiomyopathy genes and sarcomere components.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Levin

Tsao²,

Singhal³

et al. 2022

Nat Commun

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Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.

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“…Another recently completed GWAS of ascending aortic diameter (AscAoD) identified 41 independent, validated loci among UKBB participants utilizing computationally extracted aortic phenotypes from prospectively obtained cardiac magnetic resonance imaging images. 12 Imaging was analyzed using automated segmentation in up to 36 095 patients. The distribution of aortic diameters among the study population was similar to the distribution estimated in the general population.…”

Section: Clinical and Population Studies -Vbmentioning

confidence: 99%

Relationship Between Ascending Thoracic Aortic Diameter and Blood Pressure: A Mendelian Randomization Study

DePaolo

Levin

Tcheandjieu

et al. 2023

ATVB

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Background: Observational studies identified elevated blood pressure (BP) as a strong risk factor for thoracic aortic dilation, and BP reduction is the primary medical intervention recommended to prevent progression of aortic aneurysms. However, although BP may impact aortic dilation, aortic size may also impact BP. The causal relationship between BP and thoracic aortic size has not been reliably established. Methods: Genome-wide association studies summary statistics were obtained for BP and ascending thoracic aortic diameter (AscAoD). Causal effects of BP on AscAoD were estimated using 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Results: Genetically predicted increased systolic BP, diastolic BP, and mean arterial pressure all significantly associate with higher AscAoD (systolic BP: β estimate, 0.0041 mm/mm Hg [95% CI, 0.0008–0.0074]; P =0.02, diastolic BP: β estimate, 0.0272 mm/mm Hg [95% CI, 0.0224–0.0320]; P <0.001, and mean arterial pressure: β estimate, 0.0168 mm/mm Hg [95% CI, 0.0130–0.0206]; P <0.001). Genetically predicted pulse pressure, meanwhile, had an inverse association with AscAoD (β estimate, −0.0155 mm/mm Hg [95% CI, −0.0213 to −0.0096]; P <0.001). Multivariable Mendelian randomization analyses showed that genetically predicted increased mean arterial pressure and reduced pulse pressure were independently associated with AscAoD. Bidirectional Mendelian randomization demonstrated that genetically predicted AscAoD was inversely associated with pulse pressure (β estimate, −2.0721 mm Hg/mm [95% CI, −3.1137 to −1.0306]; P <0.001) and systolic BP (β estimate, −1.2878 mm Hg/mm [95% CI, −2.3533 to −0.2224]; P =0.02), while directly associated with diastolic BP (0.8203 mm Hg/mm [95% CI, 0.2735–1.3672]; P =0.004). Conclusions: BP likely contributes causally to ascending thoracic aortic dilation. Increased AscAoD likely contributes to lower systolic BP and pulse pressure, but not diastolic BP, consistent with the hemodynamic consequences of a reduced aortic diameter.

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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease

Cited by 35 publications

References 65 publications

Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Cardiovascular measures from abdominal MRI provide insights into abdominal vessel genetic architecture

Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Relationship Between Ascending Thoracic Aortic Diameter and Blood Pressure: A Mendelian Randomization Study

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