Clinical Focus

  • Pediatric Cardiology

Professional Education

  • Board Certification: American Board of Pediatrics, Pediatric Cardiology (2022)
  • Medical Education: Stanford University School of Medicine (2008) CA
  • Fellowship: Stanford University Pediatric Cardiology Fellowship (2016) CA
  • Residency: University of Washington Pediatric Residency (2011) WA
  • Board Certification: American Board of Pediatrics, Pediatrics (2011)
  • MA, University of California Berkeley, Molecular Biology (2004)

Current Research and Scholarly Interests

Over the last thirty years, our fundamental understanding of the genetics and pathogenesis of congenital heart disease has lagged the tremendous advances in the surgical and clinical care of infants with this group of disorders. With my combined research training in genomics and clinical training in pediatric cardiology I endeavor to close this gap with investigation into the genetic basis of congenital heart malformations and developing new models of disease. My goal is translate an improved molecular genetic and developmental understanding of congenital heart disease from the laboratory into clinically actionable models, diagnostics, and ultimately therapeutic interventions.

2023-24 Courses

Graduate and Fellowship Programs

All Publications

  • Epistasis regulates genetic control of cardiac hypertrophy. Research square Wang, Q., Tang, T. M., Youlton, N., Weldy, C. S., Kenney, A. M., Ronen, O., Hughes, J. W., Chin, E. T., Sutton, S. C., Agarwal, A., Li, X., Behr, M., Kumbier, K., Moravec, C. S., Tang, W. H., Margulies, K. B., Cappola, T. P., Butte, A. J., Arnaout, R., Brown, J. B., Priest, J. R., Parikh, V. N., Yu, B., Ashley, E. A. 2023


    The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.

    View details for DOI 10.21203/

    View details for PubMedID 38045390

    View details for PubMedCentralID PMC10690313

  • Epistasis regulates genetic control of cardiac hypertrophy. medRxiv : the preprint server for health sciences Wang, Q., Tang, T. M., Youlton, N., Weldy, C. S., Kenney, A. M., Ronen, O., Hughes, J. W., Chin, E. T., Sutton, S. C., Agarwal, A., Li, X., Behr, M., Kumbier, K., Moravec, C. S., Tang, W. H., Margulies, K. B., Cappola, T. P., Butte, A. J., Arnaout, R., Brown, J. B., Priest, J. R., Parikh, V. N., Yu, B., Ashley, E. A. 2023


    The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.

    View details for DOI 10.1101/2023.11.06.23297858

    View details for PubMedID 37987017

    View details for PubMedCentralID PMC10659487

  • Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome. HGG advances Blue, E. E., White, J. J., Dush, M. K., Gordon, W. W., Wyatt, B. H., White, P., Marvin, C. T., Helle, E., Ojala, T., Priest, J. R., Jenkins, M. M., Almli, L. M., Reefhuis, J., Pangilinan, F., Brody, L. C., McBride, K. L., Garg, V., Shaw, G. M., Romitti, P. A., Nembhard, W. N., Browne, M. L., Werler, M. M., Kay, D. M., Mital, S., Chong, J. X., Nascone-Yoder, N. M., Bamshad, M. J. 2023; 4 (4): 100232


    Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.

    View details for DOI 10.1016/j.xhgg.2023.100232

    View details for PubMedID 37663545

    View details for PubMedCentralID PMC10474499

  • A second update on mapping the human genetic architecture of COVID-19 NATURE Kanai, M., Andrews, S. J., Cordioli, M., Stevens, C., Neale, B. M., Daly, M., Ganna, A., Kanai, M., Andrews, S. J., Cordioli, M., Pathak, G. A., Ganna, A., Iwasaki, A., Karjalainen, J., Mehtonen, J., Pathak, G. A., Andrews, S. J., Kanai, M., Cordioli, M., Pirinen, M., Stevens, C., Chwialkowska, K., Trankiem, A., Balaconis, M. K., Veerapen, K., Wolford, B. N., Ahmad, H., Andrews, S., Puoti, K., Boer, C., Boua, P. R., Butler-Laporte, G., Cadilla, C. L., Chwialkowska, K., Colombo, F., Douillard, V., Dueker, N., Dutta, A., El-Sherbiny, Y. M., Eltoukhy, M. M., Esmaeeli, S., Faucon, A., Fave, M., Cadenas, I., Francescatto, M., Francioli, L., Franke, L., Fuentes, M., Duran, R., Cabrero, D., Harry, E. N., Jansen, P., Szentpeteri, J. L., Kaja, E., Kanai, M., Kirk, C., Kousathanas, A., Krieger, J. E., Patel, S. K., Lemacon, A., Limou, S., Lio, P., Marouli, E., Marttila, M. M., Medina-Gomez, C., Michaeli, Y., Migeotte, I., Mondal, S., Moreno-Estrada, A., Moya, L., Nakanishi, T., Nasir, J., Pasko, D., Pathak, G. A., Pearson, N. M., Pereira, A. C., Priest, J., Prijatelj, V., Prokic, I., Teumer, A., Varnai, R., Romero-Gomez, M., Roos, C., Rosenfeld, J., Ruolin, L., Schulte, E. C., Schurmann, C., Sedaghati-Khayat, B., Shaheen, D., Shivanathan, I., Sipeky, C., Sirui, Z., Striano, P., Tanigawa, Y., Remesal, A., Vadgama, N., Vallerga, C. L., Van der Laan, S., Verdugo, R. A., Wang, Q. S., Wei, Z., Zainulabid, U., Zarate, R. N., Auton, A., Shelton, J. F., Shastri, A. J., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Aslibekyan, S., O'Connell, J., Ye, C., Weldon, C. H., Hatoum, A. S., Agrawal, A., Bogdan, R., Colbert, S. C., Thompson, W. K., Fan, C., Johnson, E. C., Niazyan, L., Davidyants, M., Arakelyan, A., Avetyan, D., Bekbossynova, M., Tauekelova, A., Tuleutayev, M., Sailybayeva, A., Ramankulov, Y., Zholdybayeva, E., Dzharmukhanov, J., Kassymbek, K., Tsechoeva, T., Turebayeva, G., Smagulova, Z., Muratov, T., Khamitov, S., Kwong, A. F., Timpson, N. J., Niemi, M. K., Rahmouni, S., Guntz, J., Migeotte, I., Beguin, Y., Cordioli, M., Pigazzini, S., Nkambule, L., Georges, M., Moutschen, M., Misset, B., Darcis, G., Gofflot, S., Bouysran, Y., Busson, A., Peyrassol, X., Wilkin, F., Pichon, B., Smits, G., Vandernoot, I., Goffard, J., Tiembe, N., Nakanishi, T., Morrison, D. R., Afilalo, J., Mooser, V., Richards, J., Rousseau, S., Durand, M., Butler-Laporte, G., Forgetta, V., Laurent, L., Afrasiabi, Z., Bouab, M., Tselios, C., Xue, X., Afilalo, M., Oliveira, M., St-Cyr, J., Boisclair, A., Ragoussis, J., Auld, D., Kaufmann, D. E., Lathrop, G., Bourque, G., Decary, S., Falcone, E., Montpetit, A., Piche, A., Renoux, C., Tremblay, K., Tse, S., Zawati, M. H., Davis, L. K., Cox, N. J., Below, J. E., Sealock, J. M., Faucon, A. B., Shuey, M. M., Polikowsky, H. G., Petty, L. E., Shaw, D. M., Chen, H., Zhu, W., Schmidt, A., Ludwig, K. U., Maj, C., Rolker, S., Balla, D., Behzad, P., Nothen, M. M., Fazaal, J., Keitel, V., Keitel, V., Jensen, B., Feldt, T., Marx, N., Dreher, M., Pink, I., Cornberg, M., Illig, T., Lehmann, C., Schommers, P., Rybniker, J., Augustin, M., Knopp, L., Kurth, I., Eggermann, T., Volland, S., Berger, M. M., Brenner, T., Hinney, A., Witzke, O., Konik, M. J., Bals, R., Herr, C., Ludwig, N., Walter, J., Latz, E., Schmidt, S. V., Brooks, J. D., Bull, S., Elliott, L. T., Gagnon, F., Greenwood, C. T., Hung, R. J., Lawless, J. F., Paterson, A. D., Sun, L., Rauh, M., Briollais, L., Gingras, A., Bombard, Y., Pugh, T. J., Simpson, J., Goneau, L. W., Halevy, A. R., Maslove, D. M., Borgundvaag, B., Devine, L., Bearss, E., Richardson, D., Arnoldo, S., Friedman, S., Taher, A., Stern, S., Dagher, M., Vasilevska-Ristovska, J., Biggs, C. M., Mickiewicz, B., Strug, L. J., Scherer, S. W., Aziz, N., Jones, S. M., Knoppers, B. M., Lathrop, M., Turvey, S. E., Yeung, R. M., Allen, U., Cheung, A. M., Herridge, M. S., Hunt, M., Lerner-Ellis, J., Taher, J., Parekh, R. S., Hiraki, L. T., Cowan, J., Ducharme, F. M., Ostrowski, M., Bernier, F. P., Kellner, J., Garg, E., Yoo, S., Vlasschaert, C., Frangione, E., Chung, M., Noor, A., Greenfeld, E., Colwill, K., Clausen, M., Chao, G., Yue, F., Fritzler, M., Whitney, J., Thiruvahindrapuram, B., Garant, J., Abraham, R., Davis, A., Campigotto, A., Papenburg, J., Niranjan, K., Betschel, S., Sadarangani, M., Barton-Forbes, M., Hanley, M., Fung, C., Lapadula, E., MacDonald, G., Puopolo, M., Kaushik, D., Nirmalanathan, K., Wong, I., Khan, Z., Zarei, N., Michalowska, M., Modi, B. P., Persia, P., Estacio, A., Buchholz, M., Cheatley, P., Lorenti, M., Aman, N. F., Matveev, V., Budylowski, P., Upton, J., Morris, S., Boyd, T., Chowdhary, S., Casalino, S., Morgan, G., Mighton, C., McGeer, A., Mazzulli, T., McLeod, S. L., Binnie, A., Faghfoury, H., Chertkow, H., Racher, H., Serbanescu, M. A., Pavenski, K., Esser, M., Thompson, G., Herbrick, J., Gignoux, C. R., Wicks, S. J., Crooks, K., Barnes, K. C., Daya, M., Shortt, J., Rafaels, N., Chavan, S., Ganna, A., Schulze, T. G., Schulte, E. C., Heilbronner, U., Papiol, S., Cordioli, M., Corbetta, A., Wendtner, C. M., Spinner, C. D., Erber, J., Schneider, J., Winter, C., Wiltfang, J., Budde, M., Senner, F., Kalman, J. L., Protzer, U., Mueller, N. S., Mousas, A., Liontos, A., Christaki, E., Milionis, H., Tsilidis, K., Asimakopoulos, A., Kanellopoulou, A., Markozannes, G., Biros, D., Milionis, O., Tsourlos, S., Athanasiou, L., Kolios, N., Pappa, C., Papathanasiou, A., Pargana, E., Nasiou, M., Kosmidou, M., Rapti, I., Ntotsikas, E., Chaliasos, K., Ntzani, E., Evangelou, E., Gartzonika, K., Georgiou, I., Tzoulaki, I., Ellinghaus, D., Degenhardt, F., Caceres, M., Juzenas, S., Lenz, T. L., Albillos, A., Julia, A., Prati, D., Solligard, E., Garcia, F., Tran, F., Hanses, F., Baselli, G., Zoller, H., Holter, J., Fernandez, J., Barretina, J., Valenti, L., Bujanda, L., Romero-Gomez, M., Buti, M., D'Amato, M., Banales, J. M., Rosenstiel, P., Koehler, P., Invernizzi, P., de Cid, R., Asselta, R., Schreiber, S., Duga, S., Hehr, U., Franke, A., Maya-Miles, D., Hov, J. R., Karlsen, T. H., Folseraas, T., Teles, A., Tanck, A., Gassner, C., Azuure, C., Wacker, E., Uellendahl-Werth, F., Hemmrich-Stanisak, G., Elabd, H., Kassens, J., Arora, J., Lerga-Jaso, J., Wienbrandt, L., Ruhlemann, M., Wendorff, M., Basso, M., Vadla, M., Wittig, M., Braun, N., Lenning, O., Ozer, O., Myhre, R., Raychaudhuri, S., Wesse, T., Albrecht, W., Yi, X., Ortiz, A., de Salazar, A., Chercoles, A., Palom, A., Ruiz, A., Garcia-Fernandez, A., Blanco-Grau, A., Mantovani, A., Holten, A., Bandera, A., Cherubini, A., Protti, A., Aghemo, A., Gerussi, A., Ramirez, A., Nebel, A., Barreira, A., Lleo, A., Kildal, A., Biondi, A., Caballero-Garralda, A., Gori, A., Gluck, A., Lind, A., Nolla, A., Latiano, A., Fracanzani, A., Peschuck, A., Cavallero, A., Dyrhol-Riise, A., Ruello, A., Muscatello, A., Voza, A., Rando-Segura, A., Solier, A., Cortes, B., Mateos, B., Nafria-Jimenez, B., Schaefer, B., Bellinghausen, C., Ferrando, C., de la Horra, C., Quereda, C., Scollo, C., Lange, C., Hu, C., Paccapelo, C., Angelini, C., Cappadona, C., Bianco, C., Cea, C., Sancho, C., Hoff, D., Galimberti, D., Haschka, D., Jimenez, D., Pestana, D., Toapanta, D., Muniz-Diaz, E., Azzolini, E., Sandoval, E., Binatti, E., Scarpini, E., Casalone, E., Urrechaga, E., Paraboschi, E., Pontali, E., Reverter, E., Calderon, E. J., Navas, E., Contro, E., Arana-Arri, E., Aziz, F., Sanchez, F., Ceriotti, F., Martinelli-Boneschi, F., Peyvandi, F., Blasi, F., Malvestiti, F., Medrano, F. J., Mesonero, F., Rodriguez-Frias, F., Mueller, F., Bellani, G., Pesenti, A., Zanella, A., Grasselli, G., Pezzoli, G., Costantino, G., Albano, G., Cardamone, G., Bellelli, G., Citerio, G., Foti, G., Lamorte, G., Matullo, G., Kurihara, H., Neb, H., My, I., Hernandez, I., de Rojas, I., Galvan-Femenia, I., Afset, J., Heyckendorf, J., Damas, J., Ampuero, J., Martin, J., Erdmann, J., Badia, J., Dopazo, J., Bergan, J., Quero, J., Goikoetxea, J., Delgado, J., Guerrero, J. M., Risnes, K., Banasik, K., Mueller, K., Gaede, K. I., Garcia-Etxebarria, K., Tonby, K., Heggelund, L., Bettini, L., Sumoy, L., Terranova, L., Gustad, L., Garbarino, L., Santoro, L., Tellez, L., Roade, L., Ostadreza, M., Intxausti, M., Kogevinas, M., Riveiro-Barciela, M., Schaefer, M., Gutierrez-Stampa, M. A., Carrabba, M., Valsecchi, M. G., Hernandez-Tejero, M., Vehreschild, M. T., Manunta, M., Acosta-Herrera, M., D'Angio, M., Baldini, M., Cazzaniga, M., Marquie, M., Castoldi, M., Cecconi, M., Tomasi, M., Boada, M., Joannidis, M., Mazzocco, M., Ciccarelli, M., Rodriguez-Gandia, M., Bocciolone, M., Miozzo, M., Ayo, N., Blay, N., Chueca, N., Montano, N., Martinez, N., Cornely, O. A., Palmieri, O., Faverio, P., Preatoni, P., Bonfanti, P., Omodei, P., Tentorio, P., Castro, P., Rodrigues, P. M., Izquierdo-Sanchez, L., Espana, P., Hoffmann, P., Bacher, P., de Pablo, R., Ferrer, R., Gualtierotti, R., Gallego-Duran, R., Nieto, R., Carpani, R., Morilla, R., Badalamenti, S., Haider, S., Ciesek, S., Bombace, S., Marsal, S., Klein, S., Pelusi, S., Wilfling, S., Goerg, S., Bosari, S., Brunak, S., Heilmann-Heimbach, S., Aliberti, S., Dudman, S., Zheng, T., Bahmer, T., Pumarola, T., Cejudo, T., Rimoldi, V., Monzani, V., Skogen, V., Friaza, V., Andrade, V., Moreno, V., Peter, W., Farre, X., Khodamoradi, Y., Grimsrud, M. M., May, S., Colombo, A., Virginia, M. A., Dorador, C., Fuentes-Guajardo, M., Silva, A. X., Espinosa-Parrilla, Y., Verdugo, R. A., Yanez, C. E., Retamales-Ortega, R. M., Saez Hidalgo, J. M., Tobar-Calfucoy, E. A., Carvajal-Silva, L., Martinez, M. F., Cerpa, L. C., Christian, M. A., Cappelli, C., Valenzuela-Jorquera, H., Zapata-Contreras, D., Zuniga-Pacheco, P., Nova-Lamperti, E. A., Sanhueza, S. A., Donoso, G., Bocchieri, P., Kochifas, P., Quinones, L. A., Banasik, K., Pedersen, O., Geller, F., Westergaard, D., Sequeros, C., Nissen, J., Nielsen, S., Feldt-Rasmussen, U., Bliddal, S., Gronbaek, K., Brunak, S., Ullum, H., Ostrowski, S., Feenstra, B., Niemi, M. K., Shahin, D., El-Sherbiny, Y. M., Puoti, K., Sobh, A., Eltoukhy, M. M., Shoma, A., Cordioli, M., Corbetta, A., Nkambul, L., Elhadidy, T. A., Abd Elghafar, M. S., El-Jawhari, J. J., Mohamed, A. S., Elnagdy, M. H., Samir, A., Abdel-Aziz, M., Khafaga, W. T., El-Lawaty, W. M., Torky, M. S., El-Shanshory, M. R., Elzeiny, A., Rashad, A., Mansour, T. A., Yassen, A. M., Hegazy, M. F., Okasha, K., Eid, M. A., Hanteera, M. S., Medina-Gomez, C., Ikram, M., Uitterlinden, A. G., Ripatti, S., Jermy, B., Ruotsalainen, S., Kristiansson, K., Koskelainen, S., Perola, M., Donner, K., Kivinen, K., Palotie, A., Kaunisto, M., Julienne, H., Aschard, H., Deleuze, J., Debette, S., Tregouet, D., Abel, L., Henches, L., Lefloch, E., Claire, D., Sakuntabhai, A., Bourgeron, T., Olaso, R., Daian, D., Pellegrin, I., Casanova, J., Cobat, A., Jouanguy, E., Zhang, Q., Ghosn, J., Mentre, F., Laouenan, C., Tubiana, S., Chirouze, C., Quintana-Murci, L., Patin, E., Duffy, D., Boland, A., de Cid, R., Barretina, J., Carreras, A., Moreno, V., Kogevinas, M., Galvan-Femenia, I., Blay, N., Farre, X., Sumoy, L., Cortes, B., Mercader, J., Guindo-Martinez, M., Torrents, D., Garcia-Aymerich, J., Castano-Vinyals, G., Dobano, C., van Heel, D. A., Hunt, K. A., Trembath, R. C., Jacobs, B., Huang, Q., Martin, H. C., Mason, D., Trivedi, B., Wright, J., Munisamy, M., van Heel, D. A., Hunt, K. A., Finer, S., Griffiths, C. J., McCarthy, M. I., Rosenberger, C., Lee, J., Chang, D., Hammer, C., Hunkapiller, J., Mahajan, A., Pendergrass, R., Sucheston-Campbell, L., Yaspan, B., Lee, H., Shin, E., Jang, H., Kim, S., Kym, S., Kim, Y., Jeong, H., Kwon, K., Kim, S., Kim, J., Jang, Y., Kim, H., Lee, J., Lee, J., Lee, S., Choe, K., Kang, Y., Jee, S., Jung, K., Park, H., Kim, B., Kim, Y., Hwang, M., Yoon, K., Pairo-Castineira, E., Rawlik, K., Kousathanas, A., Caulfield, M. J., Baillie, J., Griffiths, F., Bretherick, A. D., Stuckey, A., Odhams, C. A., Walker, S., Russell, C. D., Malinauskas, T., Wu, Y., Shen, X., Elliott, K. S., Morrice, K., Keating, S., Wang, B., Rhodes, D., Klaric, L., Zechner, M., Parkinson, N., Fawkes, A., Murphy, L., Vitart, V., Wilson, J. F., Yang, J., Scott, R. H., Moutsianas, L., Law, A., Begg, C., Hendry, S., Hinds, C., Horby, P., Knight, J., Ling, L., Maslove, D., McAuley, D., Millar, J., Montgomery, H., Nichol, A., Openshaw, P. M., Pereira, A. C., Ponting, C. P., Rowan, K., Semple, M. G., Shankar-Hari, M., Summers, C., Walsh, T., Pan, J., Grau, N., Jones, T., Lim, R., Marotti, M., Whitton, C., Bociek, A., Campos, S., Arbane, G., Ostermann, M., Cha, M., DAmato, F., Kosifidou, E., Lorah, S., Morera, K., Brady, L., Hugill, K., Henning, J., Bonner, S., Headlam, E., Jones, J., List, A., Morley, J., Welford, A., Kamangu, B., Ratnakumar, A., Shoremekun, A., Alldis, Z., Astin-Chamberlain, R., Bibi, F., Biddle, J., Blow, S., Bolton, M., Borra, C., Bowles, R., Burton, M., Choudhury, Y., Cox, A., Easthope, A., Ebano, P., Fotiadis, S., Gurasashvili, J., Halls, R., Hartridge, P., Kallon, D., Kassam, J., Lancoma-Malcolm, I., Matharu, M., May, P., Mitchelmore, O., Newman, T., Patel, M., Pheby, J., Pinzuti, I., Prime, Z., Prysyazhna, O., Shiel, J., Taylor, M., Tierney, C., Zongo, O., Wood, S., Zak, A., Collier, D., Mundy, M., Thompson, C., Pritchard, L., Gellamucho, M., Cartlidge, D., Bandla, N., Bailey, L., Davies, M., Delaney, J., Scott, L., Abdelrazik, M., Alasdair, F., Carter, D., Elhassan, M., Ganesan, A., Jenkins, S., Lamond, Z., Purohit, D., Rohit, K., Saleem, M., Wall, A., Xavier, K., Bakthavatsalam, D., Gehad, K., Gnanapragasam, P., Jain, K., Jain, S., Malik, A., Pappachan, N., Moreno-Cuesta, J., Haldeos, A., Vincent, R., Oziegb, M., Cavazza, A., Cockrell, M., Corcoran, E., Depante, M., Finney, C., Jerome, E., Knighton, A., Nayak, M., Pappa, E., Saha, R., Saha, S., Dodd, A., O'Reilly, K., McPhail, M., Clarey, E., Noble, H., Smith, J., Coghlan, P., Brett, S., Gordon, A., Templeton, M., Antcliffe, D., Banach, D., Darnell, S., Fernandez, Z., Jepson, E., Mohammed, A., Rojo, R., Arias, S., Gurung, A., Wong, J., Fernandez-Roman, J., Hamilton, D. O., Johnson, E., Johnston, B., Martinez, M., Mulla, S., Waite, A. 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Place, M., Kaye, C., Benyon, S., Marriott, S., Park, L., Quinn, H., Skyes, D., Zitter, L., Baines, K., Gordon, E., Keenan, S., Pitt, A., Duffy, K., Ireland, J., Semple, G., Turner, L., Cathcart, S., Rimmer, D., Puxty, A., Puxty, K., Hurst, A., Miller, J., Speirs, S., Walker, L., Bradshaw, Z., Brown, J., Melling, S., Preston, S., Slawson, N., Warden, S., Beasley, A., Stoddard, E., Benham, L., Cupitt, J., Caswell, M., Elawamy, L., Wignall, A., Roberts, B., Golding, H., Leggett, S., Male, M., Marani, M., Prager, K., Williams, T., Golder, K., Jones, O., Cusack, R., Bolger, C., Burnish, R., Carter, M., Jackson, S., Salmon, K., Biss, J., Aquino, M., Croft, M., Frost, V., White, I., Govender, K., Webb, N., Stapleton, L., Wells, C., Nikitas, N., Sanchez-Rodriguez, A., Spencer, K., Stowe, B., Izzard, Y., Poole, M., Monnery, S., Trotman, S., Beech, V., Combes, E., Joefield, T., Covernton, P., Savage, S., Woodward, E., Camsooksai, J., Reschreiter, H., Barclay, C., Death, Y., Dube, J., Humphrey, C., Jenkins, S., Langridge, E., Milne, R., Wadams, B., Woolcock, M., Brett, M., Digby, B., Gemmell, L., Hornsby, J., MacGoey, P., O'Neil, P., Price, R., Sundaram, R., Rodden, N., Thomson, N., Rooney, K., Currie, S., Henderson, P., Ogg, B., Whiteley, S., Wilby, L., Long, K., Matthew, S., Salada, S., Trott, S., Watts, S., Friar, Z., Speight, A., Bastion, V., Chandna, H., Djeugam, B., Haseeb, M., Kent, H., Lubimbi, G., Murdoch, S., Thomas, A., David, B., Lorusso, R., Vochin, A., Penacerrada, M., Wulandari, R., Heath, C., Jakkula, S., Morris, A., Ahmed, A., Nune, A., Buttriss, C., Whitaker, E., Davey, M., Golden, D., Acklery, A., Fernandes, F., Seaman, B., Earl, V., Collins, A., Khaliq, W., Adam, R., Treus, E., Holland, S., Alfonso, J., Blackledge, B., Bruce, M., Durrans, L., Eltayeb, A., Harris, J., Hey, S., Hruska, M., Lamb, T., Rothwell, J., Fitzgerald, A., Lindergard, G., T-Michael, H., Duncan, T., Baxter-Dore, S., Cooper, L., Fox, C., Guerin, J., Hodgkiss, T., Connolly, K., McAlinden, 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S., Sarma, G., Solomonson, M., Cheng, N., Lu, W., Churchhouse, C., Goldstein, J. I., King, D., Zhou, W., Seed, C., Daly, M. J., Neale, B. M., Finucane, H., Bryant, S., Satterstrom, F., Band, G., Earle, S. G., Lin, S., Arning, N., Koelling, N., Armstrong, J., Rudkin, J. K., Callier, S., Bryant, S., Cusick, C., Fernandez-Cadenas, I., Planas, A. M., Perez-Tur, J., Llucia-Carol, L., Cullell, N., Muino, E., Carcel-Marquez, J., DeDiego, M. L., Iglesias, L., Soriano, A., Rico, V., Aguero, D., Bedini, J. L., Lozano, F., Domingo, C., Robles, V., Ruiz-Jaen, F., Marquez, L., Gomez, J., Coto, E., Albaiceta, G. M., Garcia-Clemente, M., Dalmau, D., Arranz, M. J., Dietl, B., Serra-Llovich, A., Soler-Palacin, P., Colobran, R., Martin-Nalda, A., Parra-Martinez, A., Bernardo, D., Rojo, S., Fiz-Lopez, A., Arribas-Rodriguez, E., Cal-Sabater, P., Segura, T., Gonzalez-Villar, E., Serrano-Heras, G., Marti-Fabregas, J., Jimenez-Xarrie, E., Mimbrera, A., Masjuan, J., Garcia-Madrona, S., Dominguez-Mayoral, A., Villalonga, J., Menendez-Valladares, P., Solomonson, M., COVID-19 Host Genetics Initiative 2023; 621 (7977): E7-+

    View details for DOI 10.1038/s41586-023-06355-3

    View details for Web of Science ID 001112777800001

    View details for PubMedID 37674002

    View details for PubMedCentralID PMC10482689

  • Oligogenic Architecture of Rare Noncoding Variants Distinguishes 4 Congenital Heart Disease Phenotypes. Circulation. Genomic and precision medicine Yu, M., Aguirre, M., Jia, M., Gjoni, K., Cordova-Palomera, A., Munger, C., Amgalan, D., Rosa Ma, X., Pereira, A., Tcheandjieu, C., Seidman, C., Seidman, J., Tristani-Firouzi, M., Chung, W., Goldmuntz, E., Srivastava, D., Loos, R. J., Chami, N., Cordell, H., DreSSen, M., Mueller-Myhsok, B., Lahm, H., Krane, M., Pollard, K. S., Engreitz, J. M., Gagliano Taliun, S. A., Gelb, B. D., Priest, J. R. 2023: e003968


    BACKGROUND: Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts.METHODS: We performed reimputation of 4 CHD cohorts (n=55342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14784017 variants including 6035962 rare variants of high imputation quality as validated by whole genome sequencing.RESULTS: Meta-analysis identified 16 novel loci, including 12 rare variants, which displayed moderate or large effect sizes (median odds ratio, 3.02) for 4 separate CHD categories. Analyses of chromatin structure link 13 of the genome-wide significant loci to key genes in cardiac development; rs373447426 (minor allele frequency, 0.003 [odds ratio, 3.37 for Conotruncal heart disease]; P=1.49*10-8) is predicted to disrupt chromatin structure for 2 nearby genes BDH1 and DLG1 involved in Conotruncal development. A lead variant rs189203952 (minor allele frequency, 0.01 [odds ratio, 2.4 for left ventricular outflow tract obstruction]; P=1.46*10-8) is predicted to disrupt the binding sites of 4 transcription factors known to participate in cardiac development in the promoter of SPAG9. A tissue-specific model of chromatin conformation suggests that common variant rs78256848 (minor allele frequency, 0.11 [odds ratio, 1.4 for Conotruncal heart disease]; P=2.6*10-8) physically interacts with NCAM1 (PFDR=1.86*10-27), a neural adhesion molecule acting in cardiac development. Importantly, while each individual malformation displayed substantial heritability (observed h2 ranging from 0.26 for complex malformations to 0.37 for left ventricular outflow tract obstructive disease) the risk for different CHD malformations appeared to be separate, without genetic correlation measured by linkage disequilibrium score regression or regional colocalization.CONCLUSIONS: We describe a set of rare noncoding variants conferring significant risk for individual heart malformations which are linked to genes governing cardiac development. These results illustrate that the oligogenic basis of CHD and significant heritability may be linked to rare variants outside protein-coding regions conferring substantial risk for individual categories of cardiac malformation.

    View details for DOI 10.1161/CIRCGEN.122.003968

    View details for PubMedID 37026454

  • Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy. Circulation. Genomic and precision medicine Yu, M., Harper, A. R., Aguirre, M., Pittman, M., Tcheandjieu, C., Amgalan, D., Grace, C., Goel, A., Farrall, M., Xiao, K., Engreitz, J., Pollard, K. S., Watkins, H., Priest, J. R. 2023: e003708


    A large proportion of genetic risk remains unexplained for structural heart disease involving the interventricular septum (IVS) including hypertrophic cardiomyopathy and ventricular septal defects. This study sought to develop a reproducible proxy of IVS structure from standard medical imaging, discover novel genetic determinants of IVS structure, and relate these loci to diseases of the IVS, hypertrophic cardiomyopathy, and ventricular septal defect.We estimated the cross-sectional area of the IVS from the 4-chamber view of cardiac magnetic resonance imaging in 32 219 individuals from the UK Biobank which was used as the basis of genome wide association studies and Mendelian randomization.Measures of IVS cross-sectional area at diastole were a strong proxy for the 3-dimensional volume of the IVS (Pearson r=0.814, P=0.004), and correlated with anthropometric measures, blood pressure, and diagnostic codes related to cardiovascular physiology. Seven loci with clear genomic consequence and relevance to cardiovascular biology were uncovered by genome wide association studies, most notably a single nucleotide polymorphism in an intron of CDKN1A (rs2376620; β, 7.7 mm2 [95% CI, 5.8-11.0]; P=6.0×10-10), and a common inversion incorporating KANSL1 predicted to disrupt local chromatin structure (β, 8.4 mm2 [95% CI, 6.3-10.9]; P=4.2×10-14). Mendelian randomization suggested that inheritance of larger IVS cross-sectional area at diastole was strongly associated with hypertrophic cardiomyopathy risk (pIVW=4.6×10-10) while inheritance of smaller IVS cross-sectional area at diastole was associated with risk for ventricular septal defect (pIVW=0.007).Automated estimates of cross-sectional area of the IVS supports discovery of novel loci related to cardiac development and Mendelian disease. Inheritance of genetic liability for either small or large IVS, appears to confer risk for ventricular septal defect or hypertrophic cardiomyopathy, respectively. These data suggest that a proportion of risk for structural and congenital heart disease can be localized to the common genetic determinants of size and shape of cardiovascular anatomy.

    View details for DOI 10.1161/CIRCGEN.122.003708

    View details for PubMedID 37017090

  • Relationship Between Ascending Thoracic Aortic Diameter and Blood Pressure: A Mendelian Randomization Study. Arteriosclerosis, thrombosis, and vascular biology DePaolo, J., Levin, M. G., Tcheandjieu, C., Priest, J., Gill, D., Burgess, S., Damrauer, S. M., Chirinos, J. A. 2023


    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.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.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).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.

    View details for DOI 10.1161/ATVBAHA.122.318149

    View details for PubMedID 36601961

  • Machine Learning for Automated Mitral Regurgitation Detection from Cardiac Imaging Xiao, K., Learned-Miller, E., Kalogerakis, E., Priest, J., Fiterau, M., Greenspan, H., Madabhushi, A., Mousavi, P., Salcudean, S., Duncan, J., Syeda-Mahmood, T., Taylor, R. SPRINGER INTERNATIONAL PUBLISHING AG. 2023: 236-246
  • Maternal first trimester metabolic profile in pregnancies with transposition of the great arteries. Birth defects research Huida, J., Ojala, T., Ilvesvuo, J., Surcel, H., Priest, J. R., Helle, E. 2022


    BACKGROUND: Higher maternal body mass index (BMI) and abnormal glucose metabolism during early pregnancy are associated with congenital heart defects in the offspring, but the exact mechanisms are unknown.METHODS: We evaluated the association between maternal first trimester metabolic profile and transposition of the great arteries (TGA) in the offspring in a matched case-control study with 100 TGA mothers and 200 controls born in Finland during 2004-2014. Cases and controls were matched by birth year, child sex, and maternal age and BMI. Serum samples collected between 10- and 14-weeks of gestation were analyzed for 73 metabolic measures. Conditional logistic regression was used to assess the risk for TGA in the offspring, and a subgroup analysis among mothers with high BMI was conducted.RESULTS: Higher concentrations of four subtypes of extremely large very-low-density lipoprotein (VLDL) particles and one of large VLDL particles were observed in TGA mothers. This finding did not reach statistical significance after multiple testing correction. The pooled odds ratio (OR) of the all metabolic variables was slightly higher in TGA mothers in the subgroup with maternal BMI over 25 (OR 1.25) and significantly higher in the subgroup with maternal BMI over 30 (OR 1.95) compared to the original population (OR 1.18).CONCLUSIONS: Our findings indicate that an abnormal maternal early pregnancy metabolic profile might be associated with TGA in the offspring, especially in obese mothers. A trend indicating altered VLDL subtype composition in TGA pregnancies warrants further research.

    View details for DOI 10.1002/bdr2.2139

    View details for PubMedID 36546574

  • A first update on mapping the human genetic architecture of COVID-19 NATURE Pathak, G. A., Polimanti, R., Karjalainen, J., Daly, M., Ganna, A., Daly, M. J., Stevens, C., Kanai, M., Liao, R. G., Trankiem, A., Balaconis, M. K., Nguyen, H., Solomonson, M., Veerapen, K., Ripatti, S., Nkambul, L., Bryant, S., Sankaran, V. G., Neale, B. M., Karczewski, K. J., Martin, A. R., Atkinson, E. G., Tsuo, K., Baya, N., Turley, P., Gupta, R., Walters, R. K., Palmer, D. S., Sarma, G., Cheng, N., Lu, W., Churchhouse, C., Goldstein, J., King, D., Zhou, W., Seed, C., Finucane, H., Satterstrom, F., Andrews, S. J., Sloofman, L. G., Sealfon, S. C., Hoggart, C., Underwood, S. J., Cordioli, M., Pirinen, M., Donner, K., Kivinen, K., Palotie, A., Kaunisto, M., Harerimana, N., Chwialkowska, K., Wolford, B., Roberts, G., Park, D., Ball, C. A., Coignet, M., McCurdy, S., Knight, S., Partha, R., Rhead, B., Zhang, M., Berkowitz, N., Gaddis, M., Noto, K., Ruiz, L., Pavlovic, M., Hong, E. L., Rand, K., Girshick, A., Guturu, H., Baltzell, A., Niemi, M. K., Pigazzini, S., Rahmouni, S., Georges, M., Belhaj, Y., Guntz, J., Claassen, S., Beguin, Y., Gofflot, S., Nkambule, L., Nkambul, L., Cusick, C., Moutschen, M., Misset, B., Darcis, G., Guiot, J., Azarzar, S., Malaise, O., Huynen, P., Meuris, C., Thys, M., Jacques, J., Leonard, P., Frippiat, F., Giot, J., Sauvage, A., Von Frenckell, C., Lambermont, B., Nakanishi, T., Morrison, D. R., Richards, J., Butler-Laporte, G., Forgetta, V., Ghosh, B., Laurent, L., Henry, D., Abdullah, T., Adeleye, O., Mamlouk, N., Kimchi, N., Afrasiabi, Z., Rezk, N., Vulesevic, B., Bouab, M., Guzman, C., Petitjean, L., Tselios, C., Xue, X., Afilalo, J., Adra, D., Mooser, V., Li, R., Belisle, A., Lepage, P., Ragoussis, J., Auld, D., Lathrop, G., Afilalo, M., Oliveira, M., Brenner, B., Brassard, N., Durand, M., Chasse, M., Kaufmann, D. E., Schurr, E., Hayward, C., Richmond, A., Baillie, J., Glessner, J. T., Hakonarson, H., Chang, X., Shaw, D. M., Below, J., Polikowski, H., Lauren, P. E., Chen, H., Zhu Wanying, Davis, L., Kerchberger, V., Campbell, A., Porteous, D. J., Fawns-Ritchie, C., Morris, M., McCormick, J. B., North, K., Glessner, J. R., Gignoux, C. R., Wicks, S. J., Crooks, K., Barnes, K. C., Daya, M., Shortt, J., Rafaels, N., Chavan, S., Timmers, P. J., Wilson, J. F., Tenesa, A., Kerr, S. M., D'Mellow, K., Shahin, D., El-Sherbiny, Y. M., El-Jawhari, J. J., von Hohenstaufen, K., Sobh, A., Eltoukhy, M. M., Mohamed, A. S., Elhadidy, T. A., Abd Elghafar, M. S., Elnagdy, M. H., Samir, A., Hegazy, M. F., Abdel-Aziz, M., Khafaga, W. T., El-Lawaty, W. M., Torky, M. S., Moahmed, H. S., El-shanshory, M. R., Yassen, A. M., Okasha, K., Eid, M. A., Medina-Gomez, C., Uitterlinden, A. 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A., Mussini, C., Tavecchia, L., Belli, M., Mancarella, S., Crotti, L., Parati, G., Rizzi, M., Maggiolo, F., Ripamonti, D., La Rovere, M., Sarzi-Braga, S., Bussotti, M., Ravaglia, S., Artuso, R., Andreucci, E., Perrella, A., Romani, D., Bergomi, P., Catena, E., Colombo, R., Vincenti, A., Ferri, C., Grassi, D., Pessina, G., Poscente, M., Di Pietro, M., Sabrina, R., Luchi, S., Dei, S., Sanarico, M., Gabbi, C., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Vecchia, M., Mantovani, S., Ludovisi, S., Zanella, I., Cossarizza, A., Parisi, S., Baratti, S., Squeo, G., Raggi, P., Marciano, C., Perna, R., Menatti, E., Lena, F., Martinelli, E., Bachetti, T., Suardi, C., Botta, G., Di Domenico, P., Barbieri, C., Tiseo, G., Falcone, M., Acquilini, D., Segala, F., Petrocelli, P., Baroni, S., van Heel, D. A., Hunt, K. A., van Heel, D., Trembath, R. C., Huang, Q., Martin, H. C., Mason, D., Wright, J., Trivedi, B., Finer, S., Akhtar, S., Anwar, M., Arciero, E., Ashraf, S., Breen, G., Chung, R., Curtis, C. J., Chowdhury, M., Colligan, G., Deloukas, P., Durham, C., Griffiths, C., Hurles, M., Hussain, S., Islam, K., Khan, A., Khan, A., Lavery, C., Lee, S., Lerner, R., MacArthur, D., MacLaughlin, B., Martin, H., Miah, S., Newman, B., Safa, N., Tahmasebi, F., Griffiths, C. J., Smith, A., Boughton, A. P., Li, K. W., LeFaive, J., Annis, A., Zollner, S., Wang, J., Beck, A., Niavarani, A., Sharififard, B., Aliannejad, R., Naderpour, Z., Amirsavadkouhi, A., Tadi, H., Aleagha, A., Ahmadi, S., Moghaddam, S., Adamsara, A., Saeedi, M., Abdollahi, H., Hosseini, A., Chariyavilaskul, P., Jantarabenjakul, W., Putchareon, O., Torvorapanit, P., Puthanakit, T., Hirankarn, N., Sodsai, P., Chamnanphon, M., Suttichet, T. B., Shotelersuk, V., Phokaew, C., Chetruengchai, W., Pongpanich, M., Suchartlikitwong, P., Nilaratanakul, V., Brumpton, B. M., Hveem, K., Asvold, B., Willer, C., Rogne, T., Solligard, E., Franke, L., Claringbould, A., Lopera, E., Warmerdam, R., van Blokland, I., Boezen, M., Deelen, P., Vonk, J. M., Lanting, P., Ori, A. S., Feng, Y., Weiss, S. T., Karlson, E. W., Woolley, A. E., Smoller, J. W., Murphy, S. N., Meigs, J. B., Green, R. C., Perez, E. F., Ascolillo, S., Thompson, R. C., Beckmann, N. D., Sebra, R. P., Gettler, K., Salib, I., Zyndorf, M., Schadt, E. E., Collins, B. L., Levy, T., Buxbaum, J. D., Britvan, B., Keller, K., Tang, L., Peruggia, M., Hiester, L. L., Niblo, K., Aksentijevich, A., Labkowsky, A., Karp, A., Zlatopolsky, M., Jordan, D. M., Chaudhary, K., Cho, J. H., Itan, Y., Do, R., Nadkarni, G. N., Preuss, M., Loos, R. F., Belbin, G. M., Abul-Husn, N. S., Kenny, E. E., Choi, S., O'Reilly, P., Charney, A. W., Huckins, L. M., Ferreira, M. R., Abecasis, G. R., Cantor, M. N., Kosmicki, J. A., Horowitz, J. E., Baras, A., Yadav, A., Leader, J. B., Gass, M. C., Justice, A. E., Chittoor, G., Josyula, N., Carey, D. J., Mirshahi, T., Hottenga, J., Bartels, M., de Geus, E. C., Nivard, M. G., Verma, A., Ritchie, M. D., Rader, D., Verma, S. S., Lucas, A., Bradford, Y., Li, B., Abedalthagafi, M., Al Harthi, F., Alsolm, E., Abu Safieh, L., Alowayn, A. M., Alqubaishi, F., Al Mutairi, A., AlBardis, H., Alotaibi, S., Fawzy, M. S., Alaamery, M., Massadeh, S., Almutairi, M., Alshareef, A., Suliman, B. A., Sawaji, M., AlMalik, A., Alqahtani, S., Baraka, D., Hasanato, R., Mangul, S., Aljawini, N., Albesher, N., Alkwai, S., Alswailm, M., Almohammed, I., Arabi, Y. M., Mahmoud, E. S., Khattab, A. K., Halawani, R. T., Alahmadey, Z. Z., Albakri, J. K., Felemban, W. A., Al-Awdah, L., Alghamdi, J., AlZahrani, D., AlDhawi, N., Almalki, F., Albeladi, M., Albader, A., AlJohani, S., Al-Afghani, H., Barhoush, E., Alghamdi, B., Jung, J., Alrashed, M., Zeberg, H., Maricic, T., Frithiof, R., Hultstrom, M., Lipcsey, M., Tardif, N., Rooyackers, O., Grip, J., Helgeland, O., Harris, J. R., Magnus, P., Lee, Y., Trogstad, L. S., Mangino, M., Spector, T. D., Emma, D., Moutsianas, L., Caulfield, M. J., Scott, R. H., Rendon, A., Kousathanas, A., Pasko, D., Walker, S., Stuckey, A., Odhams, C. A., Rhodes, D., Fowler, T., Chan, G., Arumugam, P., Wilson, D. J., Earle, S. G., Lin, S., Arning, N., Armstrong, J., Rudkin, J. K., Spencer, C. A., Koelling, N., Crook, D. W., Wyllie, D. H., O'Connell, A., Band, G., Callier, S., Soranzo, N., Zhao, J., Danesh, J., Di Angelantonio, E., Butterworth, A. S., Sun, Y., Huffman, J. E., O'Donnell, C. J., Peloso, G., Cho, K., Gaziano, J., Ho, Y., Tsao, P., Priest, J., Smieszek, S. P., Polymeropoulos, C., Polymeropoulos, V., Polymeropoulos, M. H., Przychodzen, B. P., Fernandez-Cadenas, I., Llucia-Carol, L., Cullell, N., Muino, E., Carcel-Marquez, J., Planas, A. M., Perez-Tur, J., DeDiego, M. L., Iglesias, L., Soriano, A., Rico, V., Aguero, D., Bedini, J. L., Domingo, C., Robles, V., Lozano, F., Ruiz-Jaen, F., Marquez, L., Gomez, J., Coto, E., Albaiceta, G. M., Garcia-Clemente, M., Dalmau, D., Arranz, M. J., Dietl, B., Serra-Llovich, A., Soler, P., Colobran, R., Martin-Nalda, A., Martinez, A., Bernardo, D., Fiz-Lopez, A., Arribas, E., De La Cal-Sabater, P., Rojo, S., Segura, T., Gonzalez-Villa, E., Serrano-Heras, G., Marti-Fabregas, J., Jimenez-Xarrie, E., Mimbrera, A., Masjuan, J., Garcia-Madrona, S., Dominguez-Mayoral, A., Villalonga, J., Menendez-Valladares, P., Chasman, D., Sesso, H. D., Manson, J. E., Buring, J. E., Ridker, P. M., Franco, G., Lee, S., Biesecker, L., COVID-19 Host Genetics Initiative 2022: E1-E10

    View details for DOI 10.1038/s41586-022-04826-7

    View details for Web of Science ID 000835655400013

    View details for PubMedID 35922517

    View details for PubMedCentralID PMC9352569

  • Leveraging Machine Learning for Translational Genetics of Cardiovascular Imaging. Journal of the American College of Cardiology Priest, J. R. 2022; 80 (5): 498-499

    View details for DOI 10.1016/j.jacc.2022.05.020

    View details for PubMedID 35902172

  • Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life. Nature communications Selle, J., Dinger, K., Jentgen, V., Zanetti, D., Will, J., Georgomanolis, T., Vohlen, C., Wilke, R., Kojonazarov, B., Klymenko, O., Mohr, J., V Koningsbruggen-Rietschel, S., Rhodes, C. J., Ulrich, A., Hirani, D., Nestler, T., Odenthal, M., Mahabir, E., Nayakanti, S., Dabral, S., Wunderlich, T., Priest, J., Seeger, W., Dötsch, J., Pullamsetti, S. S., Alejandre Alcazar, M. A. 2022; 13 (1): 4352


    Obesity is a pre-disposing condition for chronic obstructive pulmonary disease, asthma, and pulmonary arterial hypertension. Accumulating evidence suggests that metabolic influences during development can determine chronic lung diseases (CLD). We demonstrate that maternal obesity causes early metabolic disorder in the offspring. Here, interleukin-6 induced bronchial and microvascular smooth muscle cell (SMC) hyperproliferation and increased airway and pulmonary vascular resistance. The key anti-proliferative transcription factor FoxO1 was inactivated via nuclear exclusion. These findings were confirmed using primary SMC treated with interleukin-6 and pharmacological FoxO1 inhibition as well as genetic FoxO1 ablation and constitutive activation. In vivo, we reproduced the structural and functional alterations in offspring of obese dams via the SMC-specific ablation of FoxO1. The reconstitution of FoxO1 using IL-6-deficient mice and pharmacological treatment did not protect against metabolic disorder but prevented SMC hyperproliferation. In human observational studies, childhood obesity was associated with reduced forced expiratory volume in 1 s/forced vital capacity ratio Z-score (used as proxy for lung function) and asthma. We conclude that the interleukin-6-FoxO1 pathway in SMC is a molecular mechanism by which perinatal obesity programs the bronchial and vascular structure and function, thereby driving CLD development. Thus, FoxO1 reconstitution provides a potential therapeutic option for preventing this metabolic programming of CLD.

    View details for DOI 10.1038/s41467-022-31655-z

    View details for PubMedID 35896539

  • High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease. Nature genetics Tcheandjieu, C., Xiao, K., Tejeda, H., Lynch, J. A., Ruotsalainen, S., Bellomo, T., Palnati, M., Judy, R., Klarin, D., Kember, R. L., Verma, S., Palotie, A., Daly, M., Ritchie, M., Rader, D. J., Rivas, M. A., Assimes, T., Tsao, P., Damrauer, S., Priest, J. R. 2022


    Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.

    View details for DOI 10.1038/s41588-022-01070-7

    View details for PubMedID 35637384

  • Computational estimates of annular diameter reveal genetic determinants of mitral valve function and disease. JCI insight Yu, M., Tcheandjieu, C., Georges, A., Xiao, K., Tejeda, H., Dina, C., Le Tourneau, T., Fiterau, M., Judy, R., Tsao, N. L., Amgalan, D., Munger, C. J., Engreitz, J. M., Damrauer, S. M., Bouatia-Naji, N., Priest, J. R. 2022; 7 (3)


    The fibrous annulus of the mitral valve plays an important role in valvular function and cardiac physiology, while normal variation in the size of cardiovascular anatomy may share a genetic link with common and rare disease. We derived automated estimates of mitral valve annular diameter in the 4-chamber view from 32,220 MRI images from the UK Biobank at ventricular systole and diastole as the basis for GWAS. Mitral annular dimensions corresponded to previously described anatomical norms, and GWAS inclusive of 4 population strata identified 10 loci, including possibly novel loci (GOSR2, ERBB4, MCTP2, MCPH1) and genes related to cardiac contractility (BAG3, TTN, RBFOX1). ATAC-Seq of primary mitral valve tissue localized multiple variants to regions of open chromatin in biologically relevant cell types and rs17608766 to an algorithmically predicted enhancer element in GOSR2. We observed strong genetic correlation with measures of contractility and mitral valve disease and clinical correlations with heart failure, cerebrovascular disease, and ventricular arrhythmias. Polygenic scoring of mitral valve annular diameter in systole was predictive of risk mitral valve prolapse across 4 cohorts. In summary, genetic and clinical studies of mitral valve annular diameter revealed genetic determinants of mitral valve biology, while highlighting clinical associations. Polygenic determinants of mitral valve annular diameter may represent an independent risk factor for mitral prolapse. Overall, computationally estimated phenotypes derived at scale from medical imaging represent an important substrate for genetic discovery and clinical risk prediction.

    View details for DOI 10.1172/jci.insight.146580

    View details for PubMedID 35132965

  • Comprehensive Genetic Testing for Pediatric Hypertrophic Cardiomyopathy Reveals Clinical Management Opportunities and Syndromic Conditions. Pediatric cardiology Gal, D. B., Morales, A., Rojahn, S., Callis, T., Garcia, J., Priest, J. R., Truty, R., Vatta, M., Nussbaum, R. L., Esplin, E. D., Hollander, S. A. 2021


    Hypertrophic cardiomyopathy (HCM) has historically been diagnosed phenotypically. Through genetic testing, identification of a molecular diagnosis (MolDx) is increasingly common but the impact on pediatric patients is unknown. This was a retrospective study of next-generation sequencing data for 602 pediatric patients with a clinician-reported history of HCM. Diagnostic yield was stratified by gene and self-reported race/ethnicity. A MolDx of HCM was identified in 242 (40%) individuals. Sarcomeric genes were the highest yielding, but pathogenic and/or likely pathogenic (P/LP) variants in syndromic genes were found in 36% of individuals with a MolDx, often in patients without documented clinical suspicion for a genetic syndrome. Among all MolDx, 73% were in genes with established clinical management recommendations and 2.9% were in genes that conferred eligibility for clinical trial enrollment. Black patients were the least likely to receive a MolDx. In the current era, genetic testing can impact management of HCM, beyond diagnostics or prognostics, through disease-specific guidelines or clinical trial eligibility. Genetic testing frequently can help identify syndromes in patients for whom syndromes may not be suspected. These findings highlight the importance of pursuing broad genetic testing, independent of suspicion based on phenotype. Lower rates of MolDx in Black patients may contribute to health inequities. Further research is needed evaluating the genetics of HCM in underrepresented/underserved populations. Additionally, research related to the impact of genetic testing on clinical management of other diseases is warranted.

    View details for DOI 10.1007/s00246-021-02764-1

    View details for PubMedID 34714385

  • Disruption of Protein Quality Control of Human Ether-a-go-go Related Gene K+ Channel Results in Profound Long QT Syndrome. Heart rhythm Ledford, H. A., Ren, L., Thai, P. N., Park, S., Timofeyev, V., Sirish, P., Xu, W., Emigh, A. M., Priest, J. R., Perez, M. V., Ashley, E. A., Yarov-Yarovoy, V., Yamoah, E. N., Zhang, X., Chiamvimonvat, N. 2021


    BACKGROUND: Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previously study of human ether-a-go-go related gene (hERG)-encoded K+ channel (Kv11.1) supports an association between hERG and RING Finger Protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERGT613M) and RNF207 frameshift (RNF207G603fs) mutations. However, the underlying mechanistic underpinning remains unknown.OBJECTIVE: The purpose of the current study is to test the role of RNF207 on the function of hERG-encoded K+ channel subunits.METHODS AND RESULTS: Here, we demonstrate that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERGT613M proteins for degradation. RNF207G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERGT613M subunits and their dominant-negative effect on the wild-type (WT) subunits, ultimately resulting in decreased current density. Similar findings are shown for hERGA614V, a known dominant-negative mutant subunit. Finally, the presence of RNF207G603fs with hERGT613M results in significantly prolonged action potential durations and reduced hERG current in human pluripotent stem cell-derived cardiomyocytes.CONCLUSIONS: Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K+ channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and, consequently, cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in LQTS patients.

    View details for DOI 10.1016/j.hrthm.2021.10.005

    View details for PubMedID 34634443

  • Single-cell transcriptomic landscape of cardiac neural crest cell derivatives during development. EMBO reports Chen, W., Liu, X., Li, W., Shen, H., Zeng, Z., Yin, K., Priest, J. R., Zhou, Z. 2021: e52389


    The migratory cardiac neural crest cells (CNCCs) contribute greatly to cardiovascular development. A thorough understanding of the cell lineages, developmental chronology, and transcriptomic states of CNCC derivatives during normal development is essential for deciphering the pathogenesis of CNCC-associated congenital anomalies. Here, we perform single-cell transcriptomic sequencing of 34,131 CNCC-derived cells in mouse hearts covering eight developmental stages between E10.5 and P7. We report the presence of CNCC-derived mural cells that comprise pericytes and microvascular smooth muscle cells (mVSMCs). Furthermore, we identify the transition from the CNCC-derived pericytes to mVSMCs and the key regulators over the transition. In addition, our data support that many CNCC derivatives had already committed or differentiated to a specific lineage when migrating into the heart. We explore the spatial distribution of some critical CNCC-derived subpopulations with single-molecule fluorescence insitu hybridization. Finally, we computationally reconstruct the differentiation path and regulatory dynamics of CNCC derivatives. Our study provides novel insights into the cell lineages, developmental chronology, and regulatory dynamics of CNCC derivatives during development.

    View details for DOI 10.15252/embr.202152389

    View details for PubMedID 34569705

  • Mapping the human genetic architecture of COVID-19. Nature COVID-19 Host Genetics Initiative 2021


    The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity1,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprised of up to 49,562 COVID-19 patients from 46 studies across 19 countries. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian Randomization analyses support a causal role for smoking and body mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was made possible by the community of human genetic researchers coming together to prioritize sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

    View details for DOI 10.1038/s41586-021-03767-x

    View details for PubMedID 34237774

  • Congenital heart disease risk loci identified by genome-wide association study in European patients. The Journal of clinical investigation Lahm, H., Jia, M., DreSSen, M., Wirth, F. F., Puluca, N., Gilsbach, R., Keavney, B., Cleuziou, J., Beck, N., Bondareva, O., Dzilic, E., Burri, M., Konig, K. C., Ziegelmuller, J. A., Abou-Ajram, C., Neb, I., Zhang, Z., Doppler, S. A., Mastantuono, E., Lichtner, P., Eckstein, G., Horer, J., Ewert, P., Priest, J. R., Hein, L., Lange, R., Meitinger, T., Cordell, H. J., Muller-Myhsok, B., Krane, M. 2020


    Genetic factors undoubtedly affect the development of congenital heart disease (CHD), but still remain ill-defined. We sought to identify genetic risk factors associated with CHD and to accomplish functional analysis of single nucleotide polymorphisms (SNP)-carrying genes. We performed a genome-wide association study of 4,034 Caucasian CHD patients and 8,486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified four highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence expression of WNT3, and variant rs870142 related to septal defects is proposed to influence expression of MSX1. The expression of all four genes was analyzed during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNAseq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3 and MSX1 play an essential functional role in heart development at the embryonic and newborn stage.

    View details for DOI 10.1172/JCI141837

    View details for PubMedID 33201861

  • Inherited Extremes of Aortic Diameter Confer Risk for a Specific Class of Congenital Heart Disease. Circulation. Genomic and precision medicine Tcheandjieu, C., Zanetti, D., Yu, M., Priest, J. R. 2020

    View details for DOI 10.1161/CIRCGEN.120.003170

    View details for PubMedID 33191768

  • Adults With Mild-to-Moderate Congenital Heart Disease Demonstrate Measurable Neurocognitive Deficits. Journal of the American Heart Association Perrotta, M. L., Saha, P. n., Zawadzki, R. n., Beidelman, M. n., Ingelsson, E. n., Lui, G. K., Priest, J. R. 2020: e015379


    Background Neurocognitive impairment is a common complication of congenital heart disease (CHD) as well as acquired cardiovascular disease. Data are limited on neurocognitive function in adults with CHD (ACHD). Methods and Results A total of 1020 individuals with mild-to-moderate ACHD and 497 987 individuals without ACHD from the volunteer-based UK Biobank study underwent neurocognitive tests for fluid intelligence, reaction time, numeric memory, symbol-digit substitution, and trail making at enrollment and follow-up. Performance scores were compared before and after exclusion of preexisting stroke or coronary artery disease as measures of cerebro- and cardiovascular disease. Individuals with ACHD had significantly poorer performance on alpha-numeric trail making, a measure of visual attention and cognitive flexibility, spending 6.4 seconds longer on alpha-numeric trail making (95% CI, 3.0-9.9 seconds, P=0.002) and 2.5 seconds longer on numeric trail making (95% CI, 0.5-4.6 seconds, P=0.034), a measure of visual attention and processing speed. The ACHD cohort had modestly lower performance on symbol-digit substitution, a measure of processing speed, with 0.9 fewer correct substitutions (95% CI, - 1.5 to - 0.2 substitutions, P=0.021). After excluding preexisting stroke or coronary artery disease, individuals with ACHD continued to show poorer performance in all 6 domains (P=NS). Conclusions Individuals with mild-to-moderate ACHD had poorer neurocognitive performance, most significantly in tests of cognitive flexibility, analogous to deficits in children with CHD. These differences appear to be driven by increased burden of cerebro- and cardiovascular disease among individuals with ACHD.

    View details for DOI 10.1161/JAHA.119.015379

    View details for PubMedID 32981450

  • Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1-BP2) deletion in the UK Biobank. European journal of human genetics : EJHG Williams, S. G., Nakev, A. n., Guo, H. n., Frain, S. n., Tenin, G. n., Liakhovitskaia, A. n., Saha, P. n., Priest, J. R., Hentges, K. E., Keavney, B. D. 2020


    Deletion of a non-imprinted 500kb genomic region at chromosome 15q11.2, between breakpoints 1 and 2 of the Prader-Willi/Angelman locus (BP1-BP2 deletion), has been associated in previous studies with phenotypes including congenital cardiovascular malformations (CVM). Previous studies investigating association between BP1-BP2 deletion and CVM have tended to recruit cases with rarer and more severe CVM phenotypes; the impact of CVM on relatively unselected population cohorts, anticipated to contain chiefly less severe but commoner CHD phenotypes, is relatively unexplored. More precisely defining the impact of BP1-BP2 deletion on CVM risk could be useful to guide genetic counselling, since the deletion is frequently identified in the neurodevelopmental clinic. Using the UK Biobank (UKB) cohort of ~500,000 individuals, we identified individuals with CVM and investigated the association with deletions at the BP1-BP2 locus. In addition, we assessed the association of BP1-BP2 deletions with neuropsychiatric diagnoses, cognitive function and academic achievement. Cases of CVM had an increased prevalence of the deletion compared with controls (0.64%; OR = 1.73 [95% CI 1.08-2.75]; p = 0.03), as did those with neuropsychiatric diagnoses (0.68%; OR = 1.84 [95% CI 1.23-2.75]; p = 0.004). We conclude that BP1-BP2 deletion moderately increases the risk of the generally milder, but commoner, CVM phenotypes seen in this unselected population, in addition to its previously demonstrated association in case/control studies ascertained for CVM.

    View details for DOI 10.1038/s41431-020-0626-8

    View details for PubMedID 32327713

  • Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade. Proceedings of the National Academy of Sciences of the United States of America Wang, Y. n., Nanda, V. n., Direnzo, D. n., Ye, J. n., Xiao, S. n., Kojima, Y. n., Howe, K. L., Jarr, K. U., Flores, A. M., Tsantilas, P. n., Tsao, N. n., Rao, A. n., Newman, A. A., Eberhard, A. V., Priest, J. R., Ruusalepp, A. n., Pasterkamp, G. n., Maegdefessel, L. n., Miller, C. L., Lind, L. n., Koplev, S. n., Björkegren, J. L., Owens, G. K., Ingelsson, E. n., Weissman, I. L., Leeper, N. J. 2020


    Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.

    View details for DOI 10.1073/pnas.2006348117

    View details for PubMedID 32541024

  • Maternal Obesity and Diabetes Mellitus as Risk Factors for Congenital Heart Disease in the Offspring. Journal of the American Heart Association Helle, E. n., Priest, J. R. 2020: e011541


    Congenital heart disease (CHD) is the most common anatomical malformation occurring live-born infants and an increasing cause of morbidity and mortality across the lifespan and throughout the world. Population-based observations have long described associations between maternal cardiometabolic disorders and the risk of CHD in the offspring. Here we review the epidemiological evidence and clinical observations relating maternal obesity and diabetes mellitus to the risk of CHD offspring with particular attention to mechanistic models of maternal-fetal risk transmission and first trimester disturbances of fetal cardiac development. A deeper understanding of maternal risk factors holds the potential to improve both prenatal detection of CHD by identifying at-risk pregnancies, along with primary prevention of disease by improving preconception and prenatal treatment of at-risk mothers.

    View details for DOI 10.1161/JAHA.119.011541

    View details for PubMedID 32308111

  • A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population. PLoS genetics Tcheandjieu, C. n., Aguirre, M. n., Gustafsson, S. n., Saha, P. n., Potiny, P. n., Haendel, M. n., Ingelsson, E. n., Rivas, M. A., Priest, J. R. 2020; 16 (11): e1008802


    The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

    View details for DOI 10.1371/journal.pgen.1008802

    View details for PubMedID 33226994

  • Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries. Circulation research Liu, X. n., Chen, W. n., Li, W. n., Priest, J. R., Fu, Y. n., Pang, K. J., Ma, B. n., Han, B. n., Liu, X. n., Hu, S. n., Zhou, Z. n. 2020


    Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases (CHD). Understanding the clinical characteristics and pathogenesis of TGA is therefore urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic etiology underlying TGA remain largely unexplored. Objective: We sought to systematically examine the clinical characteristics and genetic etiology for isolated nonsyndromic TGA. Methods and Results: We recruited 249 TGA patients (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in TGA patients. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous or X-linked recessive variants. Established CHD-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had more than one candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. Conclusions: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

    View details for DOI 10.1161/CIRCRESAHA.119.315821

    View details for PubMedID 32078439

  • Ivy: Instrumental Variable Synthesis for Causal Inference Kuangy, Z., Sala, F., Sohoni, N., Wu, S., Cordova-Palomera, A., Dunnmon, J., Priest, J., Re, C., Chiappa, S., Calandra, R. ADDISON-WESLEY PUBL CO. 2020: 398–409
  • Cardiac Imaging of Aortic Valve Area from 34,287 UK Biobank Participants Reveal Novel Genetic Associations and Shared Genetic Comorbidity with Multiple Disease Phenotypes. Circulation. Genomic and precision medicine Córdova-Palomera, A. n., Tcheandjieu, C. n., Fries, J. n., Varma, P. n., Chen, V. S., Fiterau, M. n., Xiao, K. n., Tejeda, H. n., Keavney, B. n., Cordell, H. J., Tanigawa, Y. n., Venkataraman, G. n., Rivas, M. n., Ré, C. n., Ashley, E. A., Priest, J. R. 2020


    Background - The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases. Methods - From a sample of 34,287 white British-ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac MRI sequences of the aortic valve. Aortic valve area measurements were submitted to genome-wide association testing, followed by polygenic risk scoring and phenome-wide screening to identify genetic comorbidities. Results - A genome-wide association study of aortic valve area in these UK Biobank participants showed three significant associations, indexed by rs71190365 (chr13:50764607, DLEU1, p=1.8×10-9), rs35991305 (chr12:94191968, CRADD, p=3.4×10-8) and chr17:45013271:C:T (GOSR2, p=5.6×10-8). Replication on an independent set of 8,145 unrelated European-ancestry participants showed consistent effect sizes in all three loci, although rs35991305 did not meet nominal significance. We constructed a polygenic risk score for aortic valve area, which in a separate cohort of 311,728 individuals without imaging demonstrated that smaller aortic valve area is predictive of increased risk for aortic valve disease (Odds Ratio 1.14, p=2.3×10-6). After excluding subjects with a medical diagnosis of aortic valve stenosis (remaining n=308,683 individuals), phenome-wide association of >10,000 traits showed multiple links between the polygenic score for aortic valve disease and key health-related comorbidities involving the cardiovascular system and autoimmune disease. Genetic correlation analysis supports a shared genetic etiology with between aortic valve area and birthweight along with other cardiovascular conditions. Conclusions - These results illustrate the use of automated phenotyping of cardiac imaging data from the general population to investigate the genetic etiology of aortic valve disease, perform clinical prediction, and uncover new clinical and genetic correlates of cardiac anatomy.

    View details for DOI 10.1161/CIRCGEN.120.003014

    View details for PubMedID 33125279

  • Association between the 4p16 genomic locus and different types of congenital heart disease: results from adult survivors in the UK Biobank. Scientific reports Cordova-Palomera, A., Priest, J. R. 2019; 9 (1): 16515


    Congenital heart disease is the most common birth defect in newborns and the leading cause of death in infancy, affecting nearly 1% of live births. A locus in chromosome 4p16, adjacent to MSX1 and STX18, has been associated with atrial septal defects (ASD) in multiple European and Chinese cohorts. Here, genotyping data from the UK Biobank was used to test for associations between this locus and congenital heart disease in adult survivors of left ventricular outflow tract obstruction (n=164) and ASD (n=223), with a control sample of 332,788 individuals, and a meta-analysis of the new and existing ASD data was performed. The results show an association between the previously reported markers at 4p16 and risk for either ASD or left ventricular outflow tract obstruction, with effect sizes similar to the published data (OR between 1.27-1.45; all p<0.05). Differences in allele frequencies remained constant through the studied age range (40-70 years), indicating that the variants themselves do not drive lethal genetic defects. Meta-analysis shows an OR of 1.35 (95% CI: 1.25-1.46; p<10-4) for the association with ASD. The findings show that the genetic associations with ASD can be generalized to adult survivors of both ASD and left ventricular lesions. Although the 4p16 associations are statistically compelling, the mentioned alleles confer only a small risk for disease and their frequencies in this adult sample are the same as in children, likely limiting their clinical significance. Further epidemiological and functional studies may elicit factors triggering disease in interaction with the risk alleles.

    View details for DOI 10.1038/s41598-019-52969-x

    View details for PubMedID 31712678

  • Phenome-wide Burden of Copy-Number Variation in the UK Biobank. American journal of human genetics Aguirre, M., Rivas, M. A., Priest, J. 2019


    Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.

    View details for DOI 10.1016/j.ajhg.2019.07.001

    View details for PubMedID 31353025

  • Risk factors associated with the development of double-inlet ventricle congenital heart disease BIRTH DEFECTS RESEARCH Paige, S. L., Yang, W., Priest, J. R., Botto, L. D., Shaw, G. M., Collins, R., Natl Birth Defects Prevention 2019; 111 (11): 640–48

    View details for DOI 10.1002/bdr2.1501

    View details for Web of Science ID 000473561000003

  • Substantial Cardiovascular Morbidity in Adults With Lower-Complexity Congenital Heart Disease CIRCULATION Saha, P., Potiny, P., Rigdon, J., Morello, M., Tcheandjieu, C., Romfh, A., Fernandes, S. M., McElhinney, D. B., Bernstein, D., Lui, G. K., Shaw, G. M., Ingelsson, E., Priest, J. R. 2019; 139 (16): 1889–99
  • Risk factors associated with the development of double-inlet ventricle congenital heart disease. Birth defects research Paige, S. L., Yang, W., Priest, J. R., Botto, L. D., Shaw, G. M., Collins, R. T., National Birth Defects Prevention Study 2019


    BACKGROUND: Congenital heart disease (CHD) is the most common birth defect group and a significant contributor to neonatal and infant death. CHD with single ventricle anatomy, including hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), and various double-inlet ventricle (DIV) malformations, is the most complex with the highest mortality. Prenatal risk factors associated with HLHS have been studied, but such data for DIV are lacking.METHODS: We analyzed DIV cases and nonmalformed controls in the National Birth Defects Prevention Study, a case-control, multicenter population-based study of birth defects. Random forest analysis identified potential predictor variables for DIV, which were included in multivariable models to estimate effect magnitude and directionality.RESULTS: Random forest analysis identified pre-pregnancy diabetes, history of maternal insulin use, maternal total lipid intake, paternal race, and intake of several foods and nutrients as potential predictors of DIV. Logistic regression confirmed pre-pregnancy diabetes, maternal insulin use, and paternal race as risk factors for having a child with DIV. Additionally, higher maternal total fat intake was associated with a reduced risk.CONCLUSIONS: Maternal pre-pregnancy diabetes and history of insulin use were associated with an increased risk of having an infant with DIV, while maternal lipid intake had an inverse association. These novel data provide multiple metabolic pathways for investigation to identify better the developmental etiologies of DIV and suggest that public health interventions targeting diabetes prevention and management in women of childbearing age could reduce CHD risk.

    View details for PubMedID 30920163

  • Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts GENETIC EPIDEMIOLOGY Helle, E., Cordova-Palomera, A., Ojala, T., Saha, P., Potiny, P., Gustafsson, S., Ingelsson, E., Bamshad, M., Nickerson, D., Chong, J. X., Ashley, E., Priest, J. R., Univ Washington Ctr Mendelia 2019; 43 (2): 215–26

    View details for DOI 10.1002/gepi.22176

    View details for Web of Science ID 000462061900008

  • Substantial Cardiovascular Morbidity in Adults with Lower-Complexity Congenital Heart Disease. Circulation Saha, P., Potiny, P., Rigdon, J., Morello, M., Tcheandjieu, C., Romfh, A., Fernandes, S. M., McElhinney, D. B., Bernstein, D., Lui, G. K., Shaw, G. M., Ingelsson, E., Priest, J. R. 2019


    BACKGROUND: Although lower-complexity cardiac malformations constitute the majority of adult congenital heart disease (ACHD), the long-term risks of adverse cardiovascular events and relationship with conventional risk factors in this population are poorly understood. We aimed to quantify the risk of adverse cardiovascular events associated with lower-complexity ACHD that is unmeasured by conventional risk factors.METHODS: A multi-tiered classification algorithm was used to select individuals with lower-complexity ACHD and individuals without ACHD for comparison amongst >500,000 British adults in the UK Biobank (UKB). ACHD diagnoses were sub-classified as "isolated aortic valve (AoV)" and "non-complex" defects. Time-to-event analyses were conducted for primary endpoints of fatal or non-fatal acute coronary syndrome (ACS), ischemic stroke, heart failure (HF), and atrial fibrillation, and a secondary combined endpoint for major adverse cardiovascular event (MACE). Maximum follow-up time for the study period was 22 years using retrospectively and prospectively collected data from the UKB.RESULTS: We identified 2,006 individuals with lower-complexity ACHD and 497,983 unexposed individuals in the UKB (median [IQR] age at enrollment 58 [51,63]). Of the ACHD-exposed group, 59% were male; 51% were current or former smokers; 30% were obese; 69%, 41%, and 7% were diagnosed or treated for hypertension, hyperlipidemia, and diabetes respectively. After adjustment for 12 measured cardiovascular risk factors, ACHD remained strongly associated with the primary endpoints, with hazard ratios (HR) ranging from 2.0 (95% confidence interval [CI] 1.5-2.8, p<0.001) for ACS to 13.0 (95% CI 9.4-18.1, p<0.001) for HF. ACHD-exposed individuals with ≤2 cardiovascular risk factors had a 29% age-adjusted incidence rate of MACE in contrast to 13% in non-ACHD individuals with ≥5 risk factors.CONCLUSIONS: Individuals with lower-complexity ACHD had higher burden of adverse cardiovascular events relative to the general population that was unaccounted for by conventional cardiovascular risk factors. These findings highlight the need for closer surveillance of patients with mild to moderate ACHD and further investigation into management and mechanisms of cardiovascular risk unique to this growing population of high-risk adults.

    View details for PubMedID 30813762

  • Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources NUCLEIC ACIDS RESEARCH Koehler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. B., Danis, D., Gourdine, J., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., Osumi-Sutherland, D., Cipriani, V., Balhoff, J. P., Conlin, T., Blau, H., Baynam, G., Palmer, R., Gratian, D., Dawkins, H., Segal, M., Jansen, A. C., Muaz, A., Chang, W. H., Bergerson, J., Laulederkind, S. F., Yueksel, Z., Beltran, S., Freeman, A. F., Sergouniotis, P. I., Durkin, D., Storm, A. L., Hanauer, M., Brudno, M., Bello, S. M., Sincan, M., Rageth, K., Wheeler, M. T., Oegema, R., Lourghi, H., Della Rocca, M. G., Thompson, R., Castellanos, F., Priest, J., Cunningham-Rundles, C., Hegde, A., Lovering, R. C., Hajek, C., Olry, A., Notarangelo, L., Similuk, M., Zhang, X. A., Gomez-Andres, D., Lochmueller, H., Dollfus, H., Rosenzweig, S., Marwaha, S., Rath, A., Sullivan, K., Smith, C., Milner, J. D., Leroux, D., Boerkoel, C. F., Klion, A., Carter, M. C., Groza, T., Smedley, D., Haendel, M. A., Mungall, C., Robinson, P. N. 2019; 47 (D1): D1018–D1027
  • IMPACT OF CARDIAC ALGORITHM ON CYTOGENETIC TESTING Floyd, B. J., Hintz, S. R., Suarez, C. J., Cherry, A., Yu, L., Benitz, W., Priest, J. R., Wright, G. E., Bhombal, S., Davis, A., Chock, V. Y., Weigel, N., Kobayashi, D., Fluharty, B., Stevenson, D. BMJ PUBLISHING GROUP. 2019: 207
  • Weakly supervised classification of rare aortic valve malformations using unlabeled cardiac MRI sequences Nature Communications Fries, J. A., Varma, P., Chen, V. S., Xiao, K., Tejeda, H., Saha, P., Dunnmon, J., Chubb, H., Maskatia, S., Fiterau, M., Delp, S., Ashley, E., Ré, C., Priest, J. R. 2019; 10
  • Single-Cell RNA-Seq of the Developing Cardiac Outflow Tract Reveals Convergent Development of the Vascular Smooth Muscle Cells. Cell reports Liu, X. n., Chen, W. n., Li, W. n., Li, Y. n., Priest, J. R., Zhou, B. n., Wang, J. n., Zhou, Z. n. 2019; 28 (5): 1346–61.e4


    Cardiac outflow tract (OFT) is a major hotspot for congenital heart diseases. A thorough understanding of the cellular diversity, transitions, and regulatory networks of normal OFT development is essential to decipher the etiology of OFT malformations. We performed single-cell transcriptomic sequencing of 55,611 mouse OFT cells from three developmental stages that generally correspond to the early, middle, and late stages of OFT remodeling and septation. Known cellular transitions, such as endothelial-to-mesenchymal transition, have been recapitulated. In particular, we identified convergent development of the vascular smooth muscle cell (VSMC) lineage where intermediate cell subpopulations were found to be involved in either myocardial-to-VSMC trans-differentiation or mesenchymal-to-VSMC transition. Finally, we uncovered transcriptional regulators potentially governing cellular transitions. Our study provides a single-cell reference map of cell states for normal OFT development and paves the way for further studies of the etiology of OFT malformations at the single-cell level.

    View details for DOI 10.1016/j.celrep.2019.06.092

    View details for PubMedID 31365875

  • Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts. Genetic epidemiology Helle, E., Cordova-Palomera, A., Ojala, T., Saha, P., Potiny, P., Gustafsson, S., Ingelsson, E., Bamshad, M., Nickerson, D., Chong, J. X., University of Washington Center for Mendelian Genomics, Ashley, E., Priest, J. R. 2018


    Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.

    View details for PubMedID 30511478

  • Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic acids research Kohler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. O., Danis, D., Gourdine, J., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., Osumi-Sutherland, D., Cipriani, V., Balhoff, J. P., Conlin, T., Blau, H., Baynam, G., Palmer, R., Gratian, D., Dawkins, H., Segal, M., Jansen, A. C., Muaz, A., Chang, W. H., Bergerson, J., Laulederkind, S. J., Yuksel, Z., Beltran, S., Freeman, A. F., Sergouniotis, P. I., Durkin, D., Storm, A. L., Hanauer, M., Brudno, M., Bello, S. M., Sincan, M., Rageth, K., Wheeler, M. T., Oegema, R., Lourghi, H., Della Rocca, M. G., Thompson, R., Castellanos, F., Priest, J., Cunningham-Rundles, C., Hegde, A., Lovering, R. C., Hajek, C., Olry, A., Notarangelo, L., Similuk, M., Zhang, X. A., Gomez-Andres, D., Lochmuller, H., Dollfus, H., Rosenzweig, S., Marwaha, S., Rath, A., Sullivan, K., Smith, C., Milner, J. D., Leroux, D., Boerkoel, C. F., Klion, A., Carter, M. C., Groza, T., Smedley, D., Haendel, M. A., Mungall, C., Robinson, P. N. 2018


    The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website ( simplifies browsing terms and exploring clinical features, diseases, and human genes.

    View details for PubMedID 30476213

  • Ring Finger Protein 207 Degrades T613M Kv11.1 Channel Ledford, H. A., Park, S., Sirish, P., Xu, W., Emigh, A. M., Timofeyev, V., Priest, J. R., Perez, M. V., Ashley, E. A., Yarov-Yarovoy, V., Zhang, X., Chiamvimonvat, N. CELL PRESS. 2018: 625A
  • First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring. The Journal of pediatrics Helle, E. I., Biegley, P. n., Knowles, J. W., Leader, J. B., Pendergrass, S. n., Yang, W. n., Reaven, G. R., Shaw, G. M., Ritchie, M. n., Priest, J. R. 2018; 195: 275–78


    In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes.

    View details for PubMedID 29254757

    View details for PubMedCentralID PMC5869072

  • Birthweight, Type 2 Diabetes Mellitus, and Cardiovascular Disease: Addressing the Barker Hypothesis With Mendelian Randomization. Circulation. Genomic and precision medicine Zanetti, D. n., Tikkanen, E. n., Gustafsson, S. n., Priest, J. R., Burgess, S. n., Ingelsson, E. n. 2018; 11 (6): e002054


    Low birthweight has been associated with a higher risk of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease. The Barker hypothesis posits that intrauterine growth restriction resulting in lower birthweight is causal for these diseases, but causality is difficult to infer from observational studies.We performed regression analyses to assess associations of birthweight with cardiovascular disease and T2D in 237 631 individuals from the UK Biobank. Further, we assessed the causal relationship of such associations using Mendelian randomization.In the observational analyses, birthweight showed inverse associations with systolic and diastolic blood pressure (β, -0.83 and -0.26; per raw unit in outcomes and SD change in birthweight; 95% confidence interval [CI], -0.90 to -0.75 and -0.31 to -0.22, respectively), T2D (odds ratio, 0.83; 95% CI, 0.79-0.87), lipid-lowering treatment (odds ratio, 0.84; 95% CI, 0.81-0.86), and coronary artery disease (hazard ratio, 0.85; 95% CI, 0.78-0.94), whereas the associations with adult body mass index and body fat (β, 0.04 and 0.02; per SD change in outcomes and birthweight; 95% CI, 0.03-0.04 and 0.01-0.02, respectively) were positive. The Mendelian randomization analyses indicated inverse causal associations of birthweight with low-density lipoprotein cholesterol, 2-hour glucose, coronary artery disease, and T2D and positive causal association with body mass index but no associations with blood pressure.Our study indicates that lower birthweight, used as a proxy for intrauterine growth retardation, is causally related with increased susceptibility to coronary artery disease and T2D. This causal relationship is not mediated by adult obesity or hypertension.

    View details for PubMedID 29875125

  • Beyond Gene Panels: Whole Exome Sequencing for Diagnosis of Congenital Heart Disease. Circulation. Genomic and precision medicine Paige, S. L., Saha, P. n., Priest, J. R. 2018; 11 (3): e002097

    View details for PubMedID 29555674

  • A primer to clinical genome sequencing. Current opinion in pediatrics Priest, J. R. 2017; 29 (5): 513-519


    Genome sequencing is now available as a clinical diagnostic test. There is a significant knowledge and translation gap for nongenetic specialists of the processes necessary to generate and interpret clinical genome sequencing. The purpose of this review is to provide a primer on contemporary clinical genome sequencing for nongenetic specialists describing the human genome project, current techniques and applications in genome sequencing, limitations of current technology, and techniques on the horizon.As currently implemented, genome sequencing compares short pieces of an individual's genome with a reference sequence developed by the human genome project. Genome sequencing may be used for obtaining timely diagnostic information, cancer pharmacogenomics, or in clinical cases when previous genetic testing has not revealed a clear diagnosis. At present, the implementation of clinical genome sequencing is limited by the availability of clinicians qualified for interpretation, and current techniques in used clinical testing do not detect all types of genetic variation present in a single genome.Clinicians considering a genetic diagnosis have wide array of testing choices which now includes genome sequencing. Although not a comprehensive test in its current form, genome sequencing offers more information than gene-panel or exome sequencing and has the potential to replace targeted single-gene or gene-panel testing in many clinical scenarios.

    View details for DOI 10.1097/MOP.0000000000000532

    View details for PubMedID 28786837

    View details for PubMedCentralID PMC5590671

  • Transcriptomic Profiling Maps Anatomically Patterned Subpopulations among Single Embryonic Cardiac Cells DEVELOPMENTAL CELL Li, G., Xu, A., Sim, S., Priest, J. R., Tian, X., Khan, T., Quertermous, T., Zhou, B., Tsao, P. S., Quake, S. R., Wu, S. M. 2016; 39 (4): 491-507


    Embryonic gene expression intricately reflects anatomical context, developmental stage, and cell type. To address whether the precise spatial origins of cardiac cells can be deduced solely from their transcriptional profiles, we established a genome-wide expression database from 118, 949, and 1,166 single murine heart cells at embryonic day 8.5 (e8.5), e9.5, and e10.5, respectively. We segregated these cells by type using unsupervised bioinformatics analysis and identified chamber-specific genes. Using a random forest algorithm, we reconstructed the spatial origin of single e9.5 and e10.5 cardiomyocytes with 92.0% ± 3.2% and 91.2% ± 2.8% accuracy, respectively (99.4% ± 1.0% and 99.1% ± 1.1% if a ±1 zone margin is permitted) and predicted the second heart field distribution of Isl-1-lineage descendants. When applied to Nkx2-5(-/-) cardiomyocytes from murine e9.5 hearts, we showed their transcriptional alteration and lack of ventricular phenotype. Our database and zone classification algorithm will enable the discovery of novel mechanisms in early cardiac development and disease.

    View details for DOI 10.1016/j.devcel.2016.10.014

    View details for Web of Science ID 000389162800013

    View details for PubMedID 27840109

  • Early somatic mosaicism is a rare cause of long-QT syndrome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Priest, J. R., Gawad, C., Kahlig, K. M., Yu, J. K., O'Hara, T., Boyle, P. M., Rajamani, S., Clark, M. J., Garcia, S. T., Ceresnak, S., Harris, J., Boyle, S., Dewey, F. E., Malloy-Walton, L., Dunn, K., Grove, M., Perez, M. V., Neff, N. F., Chen, R., Maeda, K., Dubin, A., Belardinelli, L., West, J., Antolik, C., Macaya, D., Quertermous, T., Trayanova, N. A., Quake, S. R., Ashley, E. A. 2016; 113 (41): 11555-11560


    Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

    View details for DOI 10.1073/pnas.1607187113

    View details for PubMedID 27681629

  • Standards of Evidence and Mechanistic Inference in Autosomal Recessive Hypercholesterolemia ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Priest, J. R., Knowles, J. W. 2016; 36 (8): 1465-1466

    View details for DOI 10.1161/ATVBAHA.116.307714

    View details for Web of Science ID 000381474000002

    View details for PubMedID 27466618

  • Prepregnancy Diabetes and Offspring Risk of Congenital Heart Disease A Nationwide Cohort Study CIRCULATION Oyen, N., Diaz, L. J., Leirgul, E., Boyd, H. A., Priest, J., Mathiesen, E. R., Quertermous, T., Wohlfahrt, J., Melbye, M. 2016; 133 (23): 2243-2253


    Maternal diabetes mellitus is associated with an increased risk of offspring congenital heart defects (CHD); however, the causal mechanism is poorly understood. We further investigated this association in a Danish nationwide cohort.In a national cohort study, we identified 2 025 727 persons born from 1978 to 2011; among them were 7296 (0.36%) persons exposed to maternal pregestational diabetes mellitus. Pregestational diabetes mellitus was identified by using the National Patient Register and individual-level information on all prescriptions filled in Danish pharmacies. Persons with CHD (n=16 325) were assigned to embryologically related cardiac phenotypes. The CHD prevalence in the offspring of mothers with pregestational diabetes mellitus was 318 per 10 000 live births (n=232) in comparison with a baseline risk of 80 per 10 000; the adjusted relative risk for CHD was 4.00 (95% confidence interval, 3.51-4.53). The association was not modified by year of birth, maternal age at diabetes onset, or diabetes duration, and CHD risks associated with type 1 (insulin-dependent) and type 2 (insulin-independent) diabetes mellitus did not differ significantly. Persons born to women with previous acute diabetes complications had a higher CHD risk than those exposed to maternal diabetes mellitus without complications (relative risk, 7.62; 95% confidence interval, 5.23-10.6, and relative risk, 3.49; 95% confidence interval, 2.91-4.13, respectively; P=0.0004). All specific CHD phenotypes were associated with maternal pregestational diabetes mellitus (relative risk range, 2.74-13.8).The profoundly increased CHD risk conferred by maternal pregestational diabetes mellitus neither changed over time nor differed by diabetes subtype. The association with acute pregestational diabetes complications was particularly strong, suggesting a role for glucose in the causal pathway.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017465

    View details for Web of Science ID 000377439900007

    View details for PubMedID 27166384

    View details for PubMedCentralID PMC4890838

  • De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS genetics Priest, J. R., Osoegawa, K., Mohammed, N., Nanda, V., Kundu, R., Schultz, K., Lammer, E. J., Girirajan, S., Scheetz, T., Waggott, D., Haddad, F., Reddy, S., Bernstein, D., Burns, T., Steimle, J. D., Yang, X. H., Moskowitz, I. P., Hurles, M., Lifton, R. P., Nickerson, D., Bamshad, M., Eichler, E. E., Mital, S., Sheffield, V., Quertermous, T., Gelb, B. D., Portman, M., Ashley, E. A. 2016; 12 (4)


    Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

    View details for DOI 10.1371/journal.pgen.1005963

    View details for PubMedID 27058611

  • Medical implications of technical accuracy in genome sequencing. Genome medicine Goldfeder, R. L., Priest, J. R., Zook, J. M., Grove, M. E., Waggott, D., Wheeler, M. T., Salit, M., Ashley, E. A. 2016; 8 (1): 24-?


    As whole exome sequencing (WES) and whole genome sequencing (WGS) transition from research tools to clinical diagnostic tests, it is increasingly critical for sequencing methods and analysis pipelines to be technically accurate. The Genome in a Bottle Consortium has recently published a set of benchmark SNV, indel, and homozygous reference genotypes for the pilot whole genome NIST Reference Material based on the NA12878 genome.We examine the relationship between human genome complexity and genes/variants reported to be associated with human disease. Specifically, we map regions of medical relevance to benchmark regions of high or low confidence. We use benchmark data to assess the sensitivity and positive predictive value of two representative sequencing pipelines for specific classes of variation.We observe that the accuracy of a variant call depends on the genomic region, variant type, and read depth, and varies by analytical pipeline. We find that most false negative WGS calls result from filtering while most false negative WES variants relate to poor coverage. We find that only 74.6% of the exonic bases in ClinVar and OMIM genes and 82.1% of the exonic bases in ACMG-reportable genes are found in high-confidence regions. Only 990 genes in the genome are found entirely within high-confidence regions while 593 of 3,300 ClinVar/OMIM genes have less than 50% of their total exonic base pairs in high-confidence regions. We find greater than 77 % of the pathogenic or likely pathogenic SNVs currently in ClinVar fall within high-confidence regions. We identify sites that are prone to sequencing errors, including thousands present in publicly available variant databases. Finally, we examine the clinical impact of mandatory reporting of secondary findings, highlighting a false positive variant found in BRCA2.Together, these data illustrate the importance of appropriate use and continued improvement of technical benchmarks to ensure accurate and judicious interpretation of next-generation DNA sequencing results in the clinical setting.

    View details for DOI 10.1186/s13073-016-0269-0

    View details for PubMedID 26932475

    View details for PubMedCentralID PMC4774017

  • Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS Priest, J. R., Yang, W., Reaven, G., Knowles, J. W., Shaw, G. M. 2015; 169 (12): 1112-1116


    There is a well-described association between maternal diabetes mellitus and risk of congenital heart disease (CHD) in offspring. Although the clinical diagnoses of type 2 diabetes or gestational diabetes are strong risk factors for CHD, subclinical abnormalities of glucose and insulin metabolism are common within the general population and could also confer risk for CHD. We hypothesize that continuous measures of blood analytes related to maternal diabetes are related to odds of cardiac malformations.To explore the potential association of 2 different CHD phenotypes in offspring with maternal midpregnancy measures of glucose and insulin.Case-control study from a population-based cohort of 277 pregnant women in southern and central California carrying infants with tetralogy of Fallot (TOF) (n = 55), dextrotransposition of the great arteries (dTGA) (n = 42), or healthy infants without CHD (n = 180). Serum samples were collected from 2003 through 2007. The analysis was conducted from March through June 2015.Blood analytes related to maternal glucose metabolism were measured from random nonfasting second-trimester blood samples. We measured serum insulin levels by a validated radioimmunoassay, and we measured glucose levels. Multivariable logistic regression models estimated the association between these levels and case status.Serum glucose values were elevated in the maternal samples for offspring with TOF (median, 97.0 mg/dL [to convert to millimoles per liter, multiply by 0.0555]) relative to controls (median, 91.5 mg/dL) (P = .01, Wilcoxon rank sum test), a phenomenon not observed in the maternal samples for offspring with dTGA (median, 90.0 mg/dL) relative to controls (P = .18, Wilcoxon rank sum test). Serum insulin levels were significantly different between controls (median, 18.8 μIU/mL [to convert to picomoles per liter, multiply by 6.945]) and maternal samples for offspring with dTGA (median, 13.1 μIU/mL; P = .048, Wilcoxon rank sum test) but not with TOF (median, 14.3 μIU/mL; P = .35, Wilcoxon rank sum test). Relative to maternal blood glucose levels of infants without cardiac malformations, we observed that maternal blood glucose levels in models including insulin were strongly associated with odds of TOF (adjusted odds ratio = 7.54; 95% CI, 2.30-24.69) but not with dTGA (adjusted odds ratio = 1.16; 95% CI, 0.28-4.79).These results represent a direct correlation of glucose as a continuous variable to odds of specific cardiac malformations. The association between serum glucose and odds of TOF indicates the need for additional epidemiological and mechanistic investigations into the risk conferred by insulin signaling and glucose metabolism during early pregnancy.

    View details for DOI 10.1001/jamapediatrics.2015.2831

    View details for Web of Science ID 000366334600014

    View details for PubMedID 26457543

    View details for PubMedCentralID PMC4996656

  • Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome HUMAN MUTATION Cordeddu, V., Yin, J. C., Gunnarsson, C., Virtanen, C., Drunat, S., Lepri, F., De Luca, A., Rossi, C., Ciolfi, A., Pugh, T. J., Bruselles, A., Priest, J. R., Pennacchio, L. A., Lu, Z., Danesh, A., Quevedo, R., Hamid, A., Martinelli, S., Pantaleoni, F., Gnazzo, M., Daniele, P., Lissewski, C., Bocchinfuso, G., Stella, L., Odent, S., Philip, N., Faivre, L., Vlckova, M., Seemanova, E., Digilio, C., Zenker, M., Zampino, G., Verloes, A., Dallapiccola, B., Roberts, A. E., Cave, H., Gelb, B. D., Neel, B. G., Tartaglia, M. 2015; 36 (11): 1080-1087


    The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

    View details for DOI 10.1002/humu.22834

    View details for Web of Science ID 000362991400011

    View details for PubMedID 26173643

    View details for PubMedCentralID PMC4604019

  • Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data PLOS GENETICS Dewey, F. E., Grove, M. E., Priest, J. R., Waggott, D., Batra, P., Miller, C. L., Wheeler, M., Zia, A., Pan, C., Karzcewski, K. J., Miyake, C., Whirl-Carrillo, M., Klein, T. E., Datta, S., Altman, R. B., Snyder, M., Quertermous, T., Ashley, E. A. 2015; 11 (10)


    High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.

    View details for DOI 10.1371/journal.pgen.1005496

    View details for Web of Science ID 000364401600008

    View details for PubMedID 26448358

    View details for PubMedCentralID PMC4598191

  • Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data. PLoS genetics Dewey, F. E., Grove, M. E., Priest, J. R., Waggott, D., Batra, P., Miller, C. L., Wheeler, M., Zia, A., Pan, C., Karzcewski, K. J., Miyake, C., Whirl-Carrillo, M., Klein, T. E., Datta, S., Altman, R. B., Snyder, M., Quertermous, T., Ashley, E. A. 2015; 11 (10)


    High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.

    View details for DOI 10.1371/journal.pgen.1005496

    View details for PubMedID 26448358

  • Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing HEART RHYTHM Priest, J. R., Ceresnak, S. R., Dewey, F. E., Malloy-Walton, L. E., Dunn, K., Grove, M. E., Perez, M. V., Maeda, K., Dubin, A. M., Ashley, E. A. 2014; 11 (10): 1707-1713


    The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians.A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies.We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene.Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.

    View details for DOI 10.1016/j.hrthm.20l4.06.030

    View details for Web of Science ID 000343112200012

  • Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing. Heart rhythm Priest, J. R., Ceresnak, S. R., Dewey, F. E., Malloy-Walton, L. E., Dunn, K., Grove, M. E., Perez, M. V., Maeda, K., Dubin, A. M., Ashley, E. A. 2014; 11 (10): 1707-1713


    The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians.A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies.We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene.Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.

    View details for DOI 10.1016/j.hrthm.2014.06.030

    View details for PubMedID 24973560

  • Self-reported history of childhood smoking is associated with an increased risk for peripheral arterial disease independent of lifetime smoking burden. PloS one Priest, J. R., Nead, K. T., Wehner, M. R., Cooke, J. P., Leeper, N. J. 2014; 9 (2)


    Atherosclerotic disorders are well known to be associated with obesity, lipid profile, smoking, hypertension and other medical comorbidities, and large cohort studies have explored the childhood correlates to these adult risk factors. However, there has been little investigation into the childhood risk factors for peripheral arterial disease (PAD). We endeavored to better understand the role of smoking in childhood in the risk for PAD in a well described cohort of 1,537 adults at high risk for cardiovascular disease. In a multivariate regression model, we observed an increased risk of PAD among those who reported a history of smoking during childhood (OR = 2.86; 95% CI, 1.99-4.11; P<0.001), which remained statistically significant after controlling for lifetime smoking burden (OR = 1.55; 95% CI, 1.00-2.41; P = 0.049). Our novel observation of disproportionate risk of PAD conferred by a history of childhood smoking may reflect an unrecognized biological mechanism such as a unique susceptibility to vascular injury or an unaccounted for covariate such as secondhand smoke exposure in childhood. This observation suggests further investigation is required into the pathophysiology of smoking in the developing vasculature and the need for detailed clinical data about patterns of childhood smoking and smoke exposure.

    View details for DOI 10.1371/journal.pone.0088972

    View details for PubMedID 24558458

  • Self-reported history of childhood smoking is associated with an increased risk for peripheral arterial disease independent of lifetime smoking burden. PloS one Priest, J. R., Nead, K. T., Wehner, M. R., Cooke, J. P., Leeper, N. J. 2014; 9 (2)

    View details for DOI 10.1371/journal.pone.0088972

    View details for PubMedID 24558458

  • Ebstein anomaly and Trisomy 21: A rare association. Annals of pediatric cardiology Siehr, S. L., Punn, R., Priest, J. R., Lowenthal, A. 2014; 7 (1): 67-69


    This is a case report of a patient with Trisomy 21 with Ebstein anomaly, a ventricular septal defect, and acquired pulmonary vein stenosis; a rare combination, diagnosed during a routine neonatal examination.

    View details for DOI 10.4103/0974-2069.126569

    View details for PubMedID 24701093

    View details for PubMedCentralID PMC3959069

  • Triiodothyronine supplementation and cytokines during cardiopulmonary bypass in infants and children JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Priest, J. R., Slee, A., Olson, A. K., Ledee, D., Morrish, F., Portman, M. A. 2012; 144 (4): 938-?


    The Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC) study demonstrated a shortened time to extubation in children younger than 5 months old undergoing cardiopulmonary bypass for congenital heart surgery with triiodothyronine supplementation. Cardiopulmonary bypass precipitates a systemic inflammatory response that affects recovery, and triiodothyronine is related to cytokine mediators of inflammation. We sought to investigate the preoperative cytokine levels by age and relationship to the triiodothyronine levels and to examine the effect of the cytokine levels on the time to extubation.We measured 6 cytokines at preoperative time 0 and 6 and 24 hours after crossclamp removal in 76 subjects.The preoperative cytokine levels were related to both the triiodothyronine levels and the patient age. The postoperative cytokine levels were predictive of the triiodothyronine levels at 6, 12, 24, and 72 hours. Preoperative CCL4 was associated with an increased chance of early extubation. Inclusion of the cytokines did not change the relationship of triiodothyronine to the time to extubation, and the postoperative course of interleukin-6 was independently associated with a decreased chance of early extubation.The preoperative and postoperative cytokine levels, in particular, interleukin-1β, showed complex time-dependent relationships with triiodothyronine. The data suggest that cytokine-mediated suppression of triiodothyronine plays an important role in determining the clinical outcome after cardiopulmonary bypass.

    View details for DOI 10.1016/j.jtcvs.2012.05.063

    View details for Web of Science ID 000309111600030

    View details for PubMedID 22743177

  • Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects AMERICAN JOURNAL OF MEDICAL GENETICS PART A Priest, J. R., Girirajan, S., Vu, T. H., Olson, A., Eichler, E. E., Portman, M. A. 2012; 158A (6): 1279-1284


    Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.

    View details for DOI 10.1002/ajmg.a.35315

    View details for Web of Science ID 000304133700007

    View details for PubMedID 22529060

  • Relationships of the Location and Content of Rounds to Specialty, Institution, Patient-Census, and Team Size PLOS ONE Priest, J. R., Bereknyei, S., Hooper, K., Braddock, C. H. 2010; 5 (6)


    Existing observational data describing rounds in teaching hospitals are 15 years old, predate duty-hour regulations, are limited to one institution, and do not include pediatrics. We sought to evaluate the effect of medical specialty, institution, patient-census, and team participants upon time at the bedside and education occurring on rounds.Between December of 2007 and October of 2008 we performed 51 observations at Lucile Packard Children's Hospital, Seattle Children's Hospital, Stanford University Hospital, and the University of Washington Medical Center of 35 attending physicians. We recorded minutes spent on rounds in three location and seven activity categories, members of the care team, and patient-census.Results presented are means. Pediatric rounds had more participants (8.2 vs. 4.1 physicians, p<.001; 11.9 vs. 2.4 non-physicians, p<.001) who spent more minutes in hallways (96.9 min vs. 35.2 min, p<.001), fewer minutes at the bedside (14.6 vs. 38.2 min, p = .01) than internal medicine rounds. Multivariate regression modeling revealed that minutes at the bedside per patient was negatively associated with pediatrics (-2.77 adjusted bedside minutes; 95% CI -4.61 to -0.93; p<.001) but positively associated with the number of non-physician participants (0.12 adjusted bedside minutes per non physician participant; 95% CI 0.07 to 0.17; p = <.001). Education minutes on rounds was positively associated with the presence of an attending physician (2.70 adjusted education minutes; 95% CI 1.27 to 4.12; p<.001) and with one institution (1.39 adjusted education minutes; 95% CI 0.26 to 2.53; p = .02).Pediatricians spent less time at the bedside on rounds than internal medicine physicians due to reasons other than patient-census or the number of participants in rounds. Compared to historical data, internal medicine rounds were spent more at the bedside engaged in patient care and communication, and less upon educational activities.

    View details for DOI 10.1371/journal.pone.0011246

    View details for Web of Science ID 000279058300029

    View details for PubMedID 20574534

    View details for PubMedCentralID PMC2888591

  • A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease ATHEROSCLEROSIS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Borchert, A., Volcik, K. A., Grove, M. L., Tabor, H. K., Southwick, A., Tabibiazar, R., Sidney, S., Boerwinkle, E., Go, A. S., Iribarren, C., Hlatky, M. A., Fortmann, S. P., Myers, R. M., Kuhn, H., Riseh, N., Quertermous, T. 2008; 198 (1): 136-144


    Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.

    View details for DOI 10.1016/j.atheroscierosis.2007.09.003

    View details for Web of Science ID 000255491800016

    View details for PubMedID 17959182

    View details for PubMedCentralID PMC2440699

  • Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease HUMAN GENETICS Assimes, T. L., Knowles, J. W., Priest, J. R., Basu, A., Volcik, K. A., Southwick, A., Tabor, H. K., Hartiala, J., Allayee, H., Grove, M. L., Tabibiazar, R., Sidney, S., Fortmann, S. P., Go, A., Hlatky, M., Iribarren, C., Boerwinkle, E., Myers, R., Risch, N., Quertermous, T. 2008; 123 (4): 399-408


    Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.

    View details for DOI 10.1007/s00439-008-0489-5

    View details for Web of Science ID 000254959600008

    View details for PubMedID 18369664

  • Brucellosis and sacroiliitis: A common presentation of an uncommon pathogen JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE Priest, J. R., Low, D., Wang, C., Bush, T. 2008; 21 (2): 158-161


    Musculoskeletal problems are the most common chief complaint in ambulatory medicine across all specialties, and back pain is one of the top 10 problems encountered by the general practitioner. The differential diagnosis of lower back pain is exhaustive, but a history significant for constitutional symptoms or unusual exposures should prompt a work-up for an infectious cause. We describe the case of a 25-year-old man with a Brucella abortus sacroiliitis and possible orchiitis after consumption of unpasteurized cheese imported from El Salvador. The patient was successfully treated with gentamycin, rifampin, and doxycycline. Though the presentations of brucellosis are myriad, osteoarticular involvement of the axial skeleton is the most common presentation of this zoonotic infection. In the United States brucellosis is rarely encountered and is typically limited to people who are exposed during travel to endemic areas. Here we review briefly the epidemiology and presentation of a Brucella infection and current recommendations for treatment.

    View details for DOI 10.3122/jabfm.2008.02.070170

    View details for Web of Science ID 000253993300012

    View details for PubMedID 18343865

  • Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease AMERICAN HEART JOURNAL Hlatky, M. A., Quertermous, T., Boothroyd, D. B., Priest, J. R., Glassford, A. J., Myers, R. M., Fortmann, S. P., Iribarren, C., Tabor, H. K., Assimes, T. L., Tibshirani, R. J., Go, A. S. 2007; 154 (6): 1035-1042


    Only some patients with coronary artery disease (CAD) develop acute myocardial infarction (MI), and emerging evidence suggests vulnerability to MI varies systematically among patients and may have a genetic component. The goal of this study was to assess whether polymorphisms in genes encoding elements of pathways mediating the response to ischemia affect vulnerability to MI among patients with underlying CAD.We prospectively identified patients at the time of their initial clinical presentation of CAD who had either an acute MI or stable exertional angina. We collected clinical data and genotyped 34 polymorphisms in 6 genes (ANGPT1, HIF1A, THBS1, VEGFA, VEGFC, VEGFR2).The 909 patients with acute MI were significantly more likely than the 466 patients with stable angina to be male, current smokers, and hypertensive, and less likely to be taking beta-blockers or statins. Three polymorphisms in HIF1A (Pro582Ser, rs11549465; rs1087314; and Thr418Ile, rs41508050) were significantly more common in patients who presented with stable exertional angina rather than acute MI, even after statistical adjustment for cardiac risk factors and medications. The HIF-mediated transcriptional activity was significantly lower when HIF1A null fibroblasts were transfected with variant HIF1A alleles than with wild-type HIF1A alleles.Polymorphisms in HIF1A were associated with development of stable exertional angina rather than acute MI as the initial clinical presentation of CAD.

    View details for DOI 10.1016/j.ahj.2007.07.042

    View details for Web of Science ID 000251396200006

    View details for PubMedID 18035072

  • Comparative genomics: a tool to functionally annotate human DNA. Methods in molecular biology (Clifton, N.J.) Cheng, J., Priest, J. R., Pennacchio, L. A. 2007; 366: 229-251


    The availability of an increasing number of vertebrate genomes has enabled comparative methods to infer functional sequences based on evolutionary constraint. Although this has proved powerful for gene identification, significant progress has also been made in uncovering gene regulatory sequences such as distant acting transcriptional enhancers. These pursuits have led to the development of a variety of valuable databases and resources that should serve as a routine toolbox for biological discovery.

    View details for PubMedID 17568128

  • Genomic sequencing of Pleistocene cave bears SCIENCE Noonan, J. P., Hofreiter, M., Smith, D., Priest, J. R., Rohland, N., Rabeder, G., KRAUSE, J., Detter, J. C., Paabo, S., Rubin, E. M. 2005; 309 (5734): 597-600


    Despite the greater information content of genomic DNA, ancient DNA studies have largely been limited to the amplification of mitochondrial sequences. Here we describe metagenomic libraries constructed with unamplified DNA extracted from skeletal remains of two 40,000-year-old extinct cave bears. Analysis of approximately 1 megabase of sequence from each library showed that despite significant microbial contamination, 5.8 and 1.1% of clones contained cave bear inserts, yielding 26,861 base pairs of cave bear genome sequence. Comparison of cave bear and modern bear sequences revealed the evolutionary relationship of these lineages. The metagenomic approach used here establishes the feasibility of ancient DNA genome sequencing programs.

    View details for DOI 10.1126/science.1113485

    View details for Web of Science ID 000230735200044

    View details for PubMedID 15933159

  • Human-zebrafish non-coding conserved elements act in vivo to regulate transcription NUCLEIC ACIDS RESEARCH Shin, J. T., Priest, J. R., Ovcharenko, I., Ronco, A., Moore, R. K., Burns, C. G., MacRae, C. A. 2005; 33 (17): 5437-5445


    Whole genome comparisons of distantly related species effectively predict biologically important sequences--core genes and cis-acting regulatory elements (REs)--but require experimentation to verify biological activity. To examine the efficacy of comparative genomics in identification of active REs from anonymous, non-coding (NC) sequences, we generated a novel alignment of the human and draft zebrafish genomes, and contrasted this set to existing human and fugu datasets. We tested the transcriptional regulatory potential of candidate sequences using two in vivo assays. Strict selection of non-genic elements which are deeply conserved in vertebrate evolution identifies 1744 core vertebrate REs in human and two fish genomes. We tested 16 elements in vivo for cis-acting gene regulatory properties using zebrafish transient transgenesis and found that 10 (63%) strongly modulate tissue-specific expression of a green fluorescent protein reporter vector. We also report a novel quantitative enhancer assay with potential for increased throughput based on normalized luciferase activity in vivo. This complementary system identified 11 (69%; including 9 of 10 GFP-confirmed elements) with cis-acting function. Together, these data support the utility of comparative genomics of distantly related vertebrate species to identify REs and provide a scaleable, in vivo quantitative assay to define functional activity of candidate REs.

    View details for DOI 10.1093/nar/gki853

    View details for Web of Science ID 000232593700016

    View details for PubMedID 16179648

  • The DNA sequence and comparative analysis of human chromosome 5 NATURE Schmutz, J., Martin, J., Terry, A., Couronne, O., Grimwood, J., Lowry, S., Gordon, L. A., Scott, D., Xie, G., Huang, W., Hellsten, U., Tran-Gyamfi, M., She, X. W., Prabhakar, S., Aerts, A., Altherr, M., Bajorek, E., Black, S., Branscomb, E., Caoile, C., Challacombe, J. F., Chan, Y. M., Denys, M., Detter, J. C., Escobar, J., Flowers, D., Fotopulos, D., Glavina, T., Gomez, M., Gonzales, E., Goodstein, D., Grigoriev, I., Groza, M., Hammon, N., Hawkins, T., Haydu, L., Israni, S., Jett, J., Kadner, K., Kimball, H., Kobayashi, A., LOPEZ, F., Lou, Y. N., Martinez, D., Medina, C., Morgan, J., Nandkeshwar, R., Noonan, J. P., Pitluck, S., Pollard, M., Predki, P., Priest, J., Ramirez, L., Retterer, J., Rodriguez, A., Rogers, S., Salamov, A., Salazar, A., Thayer, N., Tice, H., Tsai, M., Ustaszewska, A., Vo, N., Wheeler, J., Wu, K., Yang, J., Dickson, M., Cheng, J. F., Eichler, E. E., Olsen, A., Pennacchio, L. A., Rokhsar, D. S., Richardson, P., Lucas, S. M., Myers, R. M., Rubin, E. M. 2004; 431 (7006): 268-274


    Chromosome 5 is one of the largest human chromosomes and contains numerous intrachromosomal duplications, yet it has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of noncoding conservation with non-mammalian vertebrates, suggesting that they are functionally constrained. In total, we compiled 177.7 million base pairs of highly accurate finished sequence containing 923 manually curated protein-coding genes including the protocadherin and interleukin gene families. We also completely sequenced versions of the large chromosome-5-specific internal duplications. These duplications are very recent evolutionary events and probably have a mechanistic role in human physiological variation, as deletions in these regions are the cause of debilitating disorders including spinal muscular atrophy.

    View details for DOI 10.1038/nature02919

    View details for PubMedID 15372022