Murdock, David R.
https://orcid.org/0000-0002-8536-3091
Mayo Clinic
The University of Texas Health Science Center at Houston
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.
TMEM161B regulates cerebral cortical gyration, Sonic Hedgehog signaling, and ciliary structure in the developing central nervous system
Akula, Shyam K. , Marciano, Jack H. , Lim, Youngshin , Exposito-Alonso, David , Hylton, Norma K. , Hwang, Grace H. , Neil, Jennifer E., Dominado, Nicole , Bunton-Stasyshyn, Rosie , Song, Janet , Talukdar, Maya , Schmid, Aloisia, Teboul, Lydia , Mo, Alisa , Finander, Benjamin , Beck, Samantha G., Yeh, Rebecca C., Otani, Aoi, Qian, Xuyu , DeGennaro, Ellen M. , Alkuraya, Fowzan S. , Maddirevula, Sateesh , Cascino, Gregory D. , Network, Undiagnosed Diseases, Burrage, Lindsay C. , Rosenfield, Jill A., Ketkar, Shamika , Clark, Gary, Bacino, Carlos A. , Lewis, Richard A. , Segal, Rosalind A. , Bazán, J. Fernando , Smith, K. A. , Golden, Jeffrey A. , Cho, Ginam , Walsh, Christopher A. , Alejandro, Mercedes E., Ashley, Euan A. , Baker, Eva H. , Balasubramanyam, Ashok , Barseghyan, Hayk , Batzli, Gabriel F., Bernstein, Jonathan A. , Bican, Anna, Bick, David , Birch, Camille L., Boone, Braden, Bostwick, Bret L. , Briere, Lauren C. , Brokamp, Elly , Brush, Matthew , Chen, Shan , Coakley, Terra R., Cobban, Laurel A., Colley, Heather A., Cooper, Cynthia M. , Craigen, William J., D’Souza, Precilla , Davids, Mariska, Davidson, Jean M. , Dayal, Jyoti G. , Dell’Angelica, Esteban C., Dhar, Shweta U. , Dipple, Katrina M. , Dorrani, Naghmeh, Dorset, Daniel C., Douglas, Jessica, Draper, David D., Dries, Annika M., Eckstein, David J. , Emrick, Lisa , Eng, Christine M. , Enns, Gregory M. , Eskin, Ascia , Esteves, Cecilia, Estwick, Tyra, Fernández, Liliana, Fogel, Brent L. , Friedman, Noah D., Gahl, William A. , Godfrey, Rena A., Goldstein, David B. , Gould, Sarah E., Groden, Catherine, Hamid, Rizwan , Hanchard, Neil A. , High, Frances A. , Hom, Jason , Howerton, Ellen M. , Jamal, Fariha , Jiang, Yong‐hui , Johnston, Jean M., Karaviti, Lefkothea , Kelley, Emily G., Koeller, David M. , Kohane, Isaac S. , Kohler, Jennefer N., Korrick, Susan , Kozuira, Mary, Krasnewich, Donna M., Krier, Joel B. , Lau, C. Christopher, Lazar, Jozef, LeBlanc, Kimberly , Lee, Brendan , Lee, Hane , Lewis, Richard A., Loscalzo, Joseph, Maas, Richard L., MacRae, Calum A. , Maduro, Valerie V. , Majcherska, Marta M., Malicdan, May Christine V. , Mamounas, Laura A., Manolio, Teri A. , Markello, Thomas C. , Martín, Martín G., Marwaha, Shruti , May, Thomas , McConkie‐Rosell, Allyn , McCormack, Colleen E., McCray, Alexa T. , Merker, Jason D. , Moretti, Paolo , Morimoto, Marie , Murdock, David R. , Muzny, Donna M., Nehrebecky, Michele, Nelson, Stan F., Newberry, J. Scott, Newman, John H. , Nicholas, Sarah K. , Novacic, Donna, Orengo, James P. , Pallais, J. Carl , Palmer, Christina G.S. , Papp, Jeanette C. , Parker, Neil H., Peña, Loren D.M. , Phillips, John A., Potocki, Lorraine , Pusey, Barbara N., Renteria, Genecee, Rives, Lynette, Robertson, Amy K., Rodan, Lance H. , Sampson, Jacinda B. , Samson, Susan L. , Schoch, Kelly, Shakachite, Lisa, Sharma, Prashant , Shashi, Vandana , Signer, Rebecca , Silverman, Edwin K. , Smith, Kevin S., Spillmann, Rebecca C. , Stoler, Joan M. , Sullivan, Jennifer A. , Tan, Queenie K.‐G., Tan, Wen-Haan, Toro, Camilo , Tran, Alyssa A., Urv, Tiina K. , Vogel, Tiphanie P. , Waggott, Daryl, Wahl, Colleen E., Walker, Melissa , Walley, Nicole M., Wan, Jijun , Ward, Patricia A., Westerfield, Monte, Wise, Anastasia L., Wolfe, Lynne A. , Yang, Yaping , Yoon, Amanda J., Yu, Guoyun, Zastrow, Diane B. , Zhao, Chunli , Zheng, Allison, Bunton-Stasyshyn, Rosie K , DeGennaro, Ellen M , Cascino, Gregory D , Giannini, Caterina , Burrage, Lindsay C , Rosenfield, Jill A , Bacino, Carlos , Lewis, Richard A , Segal, Rosalind A , Bazan, J Fernando , Smith, Kelly A , Golden, Jeffrey A , Cho, Ginam , Walsh, Christopher A , Alkuraya, Fowzan S , Akula, Shyam K , Shin, Taehwan , Giannini, Caterina , Network, Undiagnosed Diseases, Adams, David R. , Aday, Aaron W. , Allard, Patrick , Azamian, Mahshid S. , Beggs, Alan H. , Behnam, Babak , Bellen, Hugo J. , Berry, Gerard T. , Bonner, Devon E. , Brown, Donna M. , Burke, Elizabeth A. , Butte, Manish J. , Cogan, Joy D. , Cope, Heidi , D’Souza, Precilla , Douine, Emilie D. , Ferreira, Carlos R , Fieg, Elizabeth L. , Fisher, Paul Graham , Goldman, Alica M. , Gourdine, Jean-Philippe F. , Gropman, Andrea L , Haendel, Melissa , Holm, Ingrid A. , Huang, Yong , Jones, Angela , Kyle, Jennifer E , Lalani, Seema R , Levy, Shawn , Lewis, Richard A., Loo, Sandra K. , Macnamara, Ellen F. , Marom, Ronit , Martínez-Agosto, Julián A. , May, Thomas, Metz, Thomas , Might, Matthew , Mochida, Ganeshwaran H. , Mulvihill, John Joseph , Murphy, Jennifer L. , Muzny, Donna M. , Orange, Jordan S. , Phillips, John A., Posey, Jennifer E , Postlethwait, John H. , Reuter, Chloe M. , Rosenfeld, Jill A. , Scott, Daryl A , Sinsheimer, Janet S. , Stong, Nicholas , Sweetser, David A , Tifft, Cynthia , Vilain, Eric J. N. , Walley, Nicole M., Wangler, Michael F , Waters, Katrina M. , Webb‐Robertson, Bobbie‐Jo , Wheeler, Matthew T , Worthey, Elizabeth A. , Yamamoto, Shinya , Yang, John Jeongseok
Proceedings of the National Academy of Sciences | January 20, 2023 | Volume: 120 | Issue: 4 | Pages: No page available
Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.