Citations 2
Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve
Thériault, Sébastien , Holdcraft, Jacob A., Sharipova, Dinara , Dębiec, Radosław , Peloso, Gina M., Al‐Kassou, Baravan , Swan, Elena Ashikhmina , Ballotta, Andrea, Björck, Hanna M. , Braund, Peter S. , Corriveau, François, Dagenais, François, Francke, Michael, Gorbatov, Svetlana, Guo, Dongchuan, Habchi, Karam M, Scouarnec, Solena Le , Lichtner, Peter , Nguyen, Thy B., Norris, R., Pibarot, P, Simonet, Floriane, Tm, Sundt, Tessler, Idit , Willer, Cristen J., Wittmann, Susanne, Yang, Bo, Berezovets, Igor, Doppler, S. , Dreßen, Martina, Knoll, Katharina, Puehler, T., Schunkert, H, Bissell, Malenka M. , Bolger, Aidan, Brion, M, Citro, Rodolfo, Deeb, G. Michael, Corte, Alessandro Della, Dina, C., Eriksson, Per, Evangelista, Arturo , Franco-Cereceda, Anders, Gilon, Dan, Hetherington, Simon, Huggins, G S, Krane, Markus , Tourneau, Thierry Le, Limongelli, Giuseppe, Mathieu, P., Messika-Zeitoun, David, Michelena, Hector I., Milewicz, Dianna, Murdock, David R. , Nickenig, G., Nistri, Stefano, Nöthen, M, Samani, Nilesh J. , Schott, J., Webb, Tom R., Abdelilah-Seyfried, Salim, Schumacher, Johannes, Trenkwalder, Teresa , Body, Simon C. , Dina, Christian , Brión, Marı́a , Peloso, Gina M. , Webb, Tom R. , Faucherre, Adèle , Debiec, Radoslaw M , Peloso, Gina M , Al-Kassou, Baravan , Aranki, Sary , Ashikhmina Swan, Elena , Björck, Hanna M , Boureau, Anne Sophie , Braund, Peter S , Folkersen, Lasse , Guo, Dongchuan , Heydarpour, Mahyar , Isselbacher, Eric M , Jopling, Chris , Laporte, Fabien , Le Scouarnec, Solena , Li, Zhonglin , Lichtner, Peter , Maj, Carlo , Manikpurage, Hasanga D , Nguyen, Thy B , Norris, Russell A , Pibarot, Phillippe , Sarubbi, Berardo , Simonet, Floriane , Sundt, Thoralf , Surakka, Ida , Tessler, Idit , Yang, Bo , Doppler, Stefanie A , Dreßen, Martina , Knoll, Katharina , Puehler, Thomas , Schunkert, Heribert , Bissell, Malenka M , Bossé, Yohan , Bossone, Eduardo , Brion, María , Citro, Rodolfo , de Vincentiis, Carlo , Deeb, G Michael , Della Corte, Alessandro , Dina, Christian , Durst, Ronen , Ensminger, Stephan , Eriksson, Per , Evangelista, Arturo , Franco-Cereceda, Anders , Gilon, Dan , Giusti, Betti , Hetherington, Simon L , Huggins, Gordon S , Le Tourneau, Thierry , Limongelli, Giuseppe , Mathieu, Patrick , Messika-Zeitoun, David , Michelena, Hector I , Milewicz, Dianna M , Muehlschlegel, Jochen D , Murdock, David R , Nickenig, Georg , Nistri, Stefano , Nöthen, Markus M , Prakash, Siddharth K , Samani, Nilesh J , Jacques Schott, Jean , Webb, Tom R , Zaffran, Stéphane , Eagle, Kim , Body, Simon C , Holdcraft, Jacob A., Bellino, Michele , Dagenais, François, Forte, Amalia , Frigiola, Alessandro , Guo, Dongchuan , Isselbacher, Eric M. , Nelson, Christopher P. , Ong, Chin Siang , Roychowdhury, Tanmoy , Surakka, Ida , Willer, Cristen J , Aviérinos, Jean-François , Bolger, Aidan P. , Bossé, Yohan , Bossone, Eduardo , Citro, Rodolfo , Deeb, G. Michael , Corte, Alessandro Della , Gilon, Dan, Huggins, Gordon S. , Tourneau, Thierry Le , Mathieu, Patrick , Messika–Zeitoun, David , Nistri, Stefano , Nöthen, Markus M. , Pluchinotta, Francesca Romana , Prakash, Siddharth K. , Schott, Jean‐Jacques , Zaffran, Stéphane , Abdelilah‐Seyfried, Salim , Eagle, Kim A. , Schumacher, Johannes
Circulation | February 6, 2026 | Volume: 153 | Issue: 14 | Pages: 1060-1076
10.1161/circulationaha.125.074752
BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.
Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
Nakao, Tetsushi , Bick, Alexander G. , Taub, Margaret A. , Uddin, Md Mesbah , Niroula, Abhishek , Carty, Cara L. , Lane, John , Honigberg, Michael C. , Weinstock, Joshua S. , Pampana, Akhil , Griffin, Gabriel K. , Bhattacharya, Romit , Assimes, Themistocles L. , Emery, Leslie S. , Wong, Quenna , Broome, Jai , Laurie, Cecelia , Khan, Alyna , Smith, Albert V. , Blackwell, Thomas W. , Nelson, Christopher P. , Yoneda, Zachary T. , Peralta, Juan M. , Bowden, Donald W. , Irvin, Marguerite R. , Boorgula, Meher Preethi, Zhao, Wei , Yanek, Lisa R. , Roden, Dan M. , Reupena, Muagututi‘a Sefuiva , DeMeo, Dawn L. , Kelly, Shannon , Musani, Solomon K., Bis, Joshua C. , Lloyd‐Jones, Donald M. , Peyser, Patricia A. , Qiao, Dandi , Tiwari, Hemant K., Smith, Jennifer A. , Smith, Nicholas L. , Kelly, Tanika N. , Hidalgo, Bertha , Weeks, Daniel E. , Group, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA), Deka, Ranjan , Naseri, Take, Fuentes, Lisa de las , Raffield, Laura M. , Morrison, Alanna C. , Vries, Paul S. de , Shoemaker, M. Benjamin , Palmer, Nicholette D. , Barnes, Kathleen C. , Redline, Susan , Kardia, Sharon L.R., Becker, Lewis C. , Heckbert, Susan R. , He, Jiang , Post, Wendy S. , Arnett, Donna K. , McGarvey, Stephen T. , Chen, Yii‐Der Ida , Kaplan, Robert C. , Meyers, Deborah A. , Fornage, Myriam , Boerwinkle, Eric , Loos, Ruth J. F. , Silverman, Edwin K. , Danesh, John , Samani, Nilesh J. , Jaiswal, Siddhartha , Ebert, Benjamin L. , Reiner, Alex P. , Mathias, Rasika A. , Do, Ron , Natarajan, Pradeep , Zhao, Wei , Zekavat, Seyedeh M , Uddin, Md M , Niroula, Abhishek , Lane, John , Honigberg, Michael C , Weinstock, Joshua S , Pampana, Akhil , Griffin, Gabriel K , Clarke, Shoa L , Bhattacharya, Romit , Assimes, Themistocles L , Emery, Leslie S , Stilp, Adrienne M , Wong, Quenna , Broome, Jai , Khan, Alyna T , Smith, Albert V , Codd, Veryan , Nelson, Christopher P , Yoneda, Zachary T , Peralta, Juan M , Yanek, Lisa R , Wiggins, Kerri L , Gu, C Charles , Peloso, Gina M , Roden, Dan M. , Hwu, Chii-Min , North, Kari E. , Bis, Joshua C , Lloyd-Jones, Donald M , Johnsen, Jill M , Preuss, Michael , Tracy, Russell P , Peyser, Patricia A , Qiao, Dandi , Curran, Joanne E , Freedman, Barry I , Chavan, Sameer , Smith, Jennifer A , Kelly, Tanika N , Hidalgo, Bertha , Weeks, Daniel E , Hawley, Nicola L , Minster, Ryan L , de las Fuentes, Lisa , Raffield, Laura M , Ballantyne, Christie M , Kenny, Eimear E , Rich, Stephen S , Whitsel, Eric A , Cho, Michael H , Palmer, Nicholette D , Mitchell, Braxton D , Shuldiner, Alan R , Redline, Susan , Heckbert, Susan R , He, Jiang , Post, Wendy , Arnett, Donna K , Vasan, Ramachandran S , Weiss, Scott T , McGarvey, Stephen T , Custer, Brian S , Correa, Adolfo , Manson, JoAnn E , Konkle, Barbara A , Loos, Ruth J F , Rotter, Jerome I , Silverman, Edwin K , Kooperberg, Charles , Samani, Nilesh J , Jaiswal, Siddhartha , Libby, Peter , Ellinor, Patrick T , Pankratz, Nathan , Ebert, Benjamin L , Mathias, Rasika A , Do, Ron , Natarajan, Pradeep , Morrison, Alanna C , Bick, Alexander G , Gibson, Christopher James , Clarke, Shoa L. , Codd, Veryan , Wiggins, Kerri L. , Hixson, James E. , Peloso, Gina M. , Tracy, Russell P. , Desai, Pinkal , Curran, Joanne E. , Freedman, Barry I. , Cupples, L. Adrienne , Group, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA), Naseri, Take K. , Ballantyne, Christie M. , Rich, Stephen S. , Cho, Michael H. , Pace, Betty S. , Blangero, John , Mitchell, Braxton D. , Shuldiner, Alan R. , Abecasis, Gonçalo R. , Vasan, Ramachandran S. , Darbar, Dawood , Weiss, Scott T. , Andrade, Mariza de , Custer, Brian , Psaty, Bruce M. , Manson, JoAnn E. , Konkle, Barbara A. , Rotter, Jerome I. , Kooperberg, Charles , Libby, Peter , Ellinor, Patrick T. , Pankratz, Nathan
Science Advances | April 6, 2022 | Volume: 8 | Issue: 14 | Pages: No page available
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.