James Rush Priest

James Priest, MD

Adjunct Clinical Assistant Professor

Pediatric Cardiology

map
Lucile Packard Children's Hospital Stanford
Betty Irene Moore Children's Heart Center
725 Welch Road, Ste 120
Palo Alto, CA 94304
Teléfono: (650) 721-2121
Fax: (650) 497-8422

Localización

Lucile Packard Children's Hospital Stanford
Betty Irene Moore Children's Heart Center

725 Welch Road, Ste 120

Palo Alto, CA 94304

Mapas, direcciones y estacionamiento

Teléfono : (650) 721-2121

Fax : (650) 497-8422

Experiencia

High Cholesterol Hyperlipidemia

Hypertriglyceridemia

Rare Dyslipidemias

Trabajo y educación

Educación

Stanford University School of Medicine, Palo Alto, CA, 6/30/2008

Últimos años de residencia

University of Washington Pediatric Residency, Seattle, WA, 6/30/2011

Subespecialidad

Stanford University Pediatric Cardiology Fellowship, Palo Alto, CA, 12/31/2015

Certificado(s) de especialidad

Pediatrics, American Board of Pediatrics, 2011

Pediatric Cardiology, American Board of Pediatrics, 2022

Idiomas

English

German

Spanish

Publicaciones

Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart. medRxiv : the preprint server for health sciences Ma, X. R., Conley, S. D., Kosicki, M., Bredikhin, D., Cui, R., Tran, S., Sheth, M. U., Qiu, W. L., Chen, S., Kundu, S., Kang, H. Y., Amgalan, D., Munger, C. J., Duan, L., Dang, K., Rubio, O. M., Kany, S., Zamirpour, S., DePaolo, J., Padmanabhan, A., Olgin, J., Damrauer, S., Andersson, R., Gu, M., Priest, J. R., Quertermous, T., Qiu, X., Rabinovitch, M., Visel, A., Pennacchio, L., Kundaje, A., Glass, I. A., Gifford, C. A., Pirruccello, J. P., Goodyer, W. R., Engreitz, J. M. 2024

Abstract

Congenital heart defects (CHD) arise in part due to inherited genetic variants that alter genes and noncoding regulatory elements in the human genome. These variants are thought to act during fetal development to influence the formation of different heart structures. However, identifying the genes, pathways, and cell types that mediate these effects has been challenging due to the immense diversity of cell types involved in heart development as well as the superimposed complexities of interpreting noncoding sequences. As such, understanding the molecular functions of both noncoding and coding variants remains paramount to our fundamental understanding of cardiac development and CHD. Here, we created a gene regulation map of the healthy human fetal heart across developmental time, and applied it to interpret the functions of variants associated with CHD and quantitative cardiac traits. We collected single-cell multiomic data from 734,000 single cells sampled from 41 fetal hearts spanning post-conception weeks 6 to 22, enabling the construction of gene regulation maps in 90 cardiac cell types and states, including rare populations of cardiac conduction cells. Through an unbiased analysis of all 90 cell types, we find that both rare coding variants associated with CHD and common noncoding variants associated with valve traits converge to affect valvular interstitial cells (VICs). VICs are enriched for high expression of known CHD genes previously identified through mapping of rare coding variants. Eight CHD genes, as well as other genes in similar molecular pathways, are linked to common noncoding variants associated with other valve diseases or traits via enhancers in VICs. In addition, certain common noncoding variants impact enhancers with activities highly specific to particular subanatomic structures in the heart, illuminating how such variants can impact specific aspects of heart structure and function. Together, these results implicate new enhancers, genes, and cell types in the genetic etiology of CHD, identify molecular convergence of common noncoding and rare coding variants on VICs, and suggest a more expansive view of the cell types instrumental in genetic risk for CHD, beyond the working cardiomyocyte. This regulatory map of the human fetal heart will provide a foundational resource for understanding cardiac development, interpreting genetic variants associated with heart disease, and discovering targets for cell-type specific therapies.

View details for DOI 10.1101/2024.11.20.24317557

View details for PubMedID 39606363

View details for PubMedCentralID PMC11601760

Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defects. BMC genomics Broberg, M., Ampuja, M., Jones, S., Ojala, T., Rahkonen, O., Kivelä, R., Priest, J., Palotie, A., Ollila, H. M., Helle, E. 2024; 25 (1): 256

Abstract

Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database.We discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327.Our results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

View details for DOI 10.1186/s12864-024-10172-x

View details for PubMedID 38454350

View details for PubMedCentralID PMC10918883

Learning epistatic polygenic phenotypes with Boolean interactions. PloS one Behr, M., Kumbier, K., Cordova-Palomera, A., Aguirre, M., Ronen, O., Ye, C., Ashley, E., Butte, A. J., Arnaout, R., Brown, B., Priest, J., Yu, B. 2024; 19 (4): e0298906

Abstract

Detecting epistatic drivers of human phenotypes is a considerable challenge. Traditional approaches use regression to sequentially test multiplicative interaction terms involving pairs of genetic variants. For higher-order interactions and genome-wide large-scale data, this strategy is computationally intractable. Moreover, multiplicative terms used in regression modeling may not capture the form of biological interactions. Building on the Predictability, Computability, Stability (PCS) framework, we introduce the epiTree pipeline to extract higher-order interactions from genomic data using tree-based models. The epiTree pipeline first selects a set of variants derived from tissue-specific estimates of gene expression. Next, it uses iterative random forests (iRF) to search training data for candidate Boolean interactions (pairwise and higher-order). We derive significance tests for interactions, based on a stabilized likelihood ratio test, by simulating Boolean tree-structured null (no epistasis) and alternative (epistasis) distributions on hold-out test data. Finally, our pipeline computes PCS epistasis p-values that probabilisticly quantify improvement in prediction accuracy via bootstrap sampling on the test set. We validate the epiTree pipeline in two case studies using data from the UK Biobank: predicting red hair and multiple sclerosis (MS). In the case of predicting red hair, epiTree recovers known epistatic interactions surrounding MC1R and novel interactions, representing non-linearities not captured by logistic regression models. In the case of predicting MS, a more complex phenotype than red hair, epiTree rankings prioritize novel interactions surrounding HLA-DRB1, a variant previously associated with MS in several populations. Taken together, these results highlight the potential for epiTree rankings to help reduce the design space for follow up experiments.

View details for DOI 10.1371/journal.pone.0298906

View details for PubMedID 38625909

Genomic and transcriptomic data analyses highlight KPNB1 and MYL4 as novel risk genes for congenital heart disease Broberg, M., Ampuja, M., Jones, S., Ojala, T., Kivela, R., Priest, J., Ollila, H., Helle, E. SPRINGERNATURE. 2024: 775

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

Abstract

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/rs.3.rs-3509208/v1

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

Abstract

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

Abstract

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. 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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. 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C., Smeaton, J., Agravante, K., Krishnamurthy, V., Diaba, C., John, L., Lim, L., Jha, R., Egan, J., Felton, T., Glasgow, S., Padden, G., Choudhr, O., Bradley-Potts, J., Moss, S., Lingeswaran, S., Alexander, P., Brandwood, C., Fiouni, S., Ward, L., Allen, S., Shaw, J., Smith, C., Adanini, O., Collins, R., Msiska, M., Ofori, L., Bhatia, N., Dolan, H., Brunton, M., Caterson, J., Coles, H., Keating, L., Tilney, E., Jacques, N., Frise, M., Armistead, J., Bartley, S., Bhuie, P., Rai, S., Tomkova, G., Greer, S., Shuker, K., Tridente, A., Dobson, E., Hunt, J., Tully, R., Dearden, J., Drummond, A., Kamath, P., Bullock, E., Mulcahy, M., Munt, S., O'Connor, G., Philbin, J., Rishton, C., Scott, C., Winnard, S., Hasni, N., Gascoyne, R., Hawes, J., Pritchard, K., Stevenson, L., Whileman, A., Beavis, S., Bishop, L., Cart, C., Dale, K., Kelly-Baxter, M., Mendelski, A., Moakes, E., Smith, R., Woodward, J., Wright, S., Allan, A., Botello, A., Liew, J., Medhora, J., Trumper, E., Savage, F., Scott, T., 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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A., Elliott, P., Tenesa, A., Aitkin, E., Aravindan, L., Armstrong, R., Biggs, H., Boz, C., Brown, A., Chikowore, P., Clark, R., Coutts, A., Coyle, J., Cullum, L., Das, S., Day, N., Donnelly, L., Duncan, E., Finernan, P., Fourman, M., Furlong, A., Furniss, J., Gallagher, B., Gilchrist, T., Golightly, A., Hafezi, K., Hamilton, D., Hendry, R., Kearns, N., Law, D., Law, R., Law, S., Lidstone-Scott, R., Lauder, C., Macgillivray, L., Maclean, A., Mal, H., McCafferty, S., Mcmaster, E., Meikle, J., Moore, S. C., Murphy, S., Mybaya, H., Odam, M., Oosthuyzen, W., Zheng, C., Chen, J., Paterson, T., Tucker, P., Schon, K., Stenhouse, A., Das, M., Swets, M., Szoor-McElhinney, H., Taneski, F., Turtle, L., Wackett, T., Ward, M., Weaver, J., Wrobel, N., Rakitko, A., Ilinsky, V., Yermakovich, D., Popov, I., Chernitsov, A., Kovalenko, E., Vergasova, E., Prokhorov, A., Krasnenko, A., Plotnikov, N., Stetsenko, I., Kim, A., Cirulli, E. T., Barrett, K., Bolze, A., White, S., Washington, N. L., Lu, J. T., Riffle, S., Tanudjaja, F., Wang, X., Ramirez, J. M., Leonetti, N., Sandoval, E., Neveux, I., Dabe, S., Grzymski, J. J., Joshi, M. N., Dixit, R. D., Shah, P. K., Upadhyay, K. J., Chuhan, N. T., Desai, K. J., Shah, M. R., Modi, B., Joshi, C. G., Pandit, R. J., Singh, I., Ansari, A. I., Raval, J. N., Patel, Z. Z., Moreno-Estrada, A., Armando Vazquez-Perez, J., Castillejos-Lopez, M., Aquino-Galvez, A., Shamah-Levy, T., Avila-Arcos, M. C., Tusie Luna, M., Hidalgo-Miranda, A., Barberena-Jonas, C., Quinto-Cortes, C. D., Antonio Avila-Arcos, M., Huerta-Chagoya, A., Garcia-Garcia, L., Martinez Barnetche, J., Alpuche-Aranda, C., Rivera, J. A., Barrientos Gutierrez, T., Ochoa-Guzman, A., Luisa Ordonez-Sanchez, M., Segura-Kato, Y., Alonso Herrera-Montalvo, L., Mendoza-Vargas, A., Pablo Reyes-Grajeda, J., Cruz-Cruz, A. 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M., Maswadeh, K. B., Alsoub, F. S., AlRawashdeh, T. J., Esawi, E., Abu Alragheb, B. O., Maswadeh, A. B., Al-Kadash, A., Al-Ani, A., Alsafadi, D. B., Shahin, M. A., Al Qtaish, N., Alawneh, F. M., Abulail, J. A., Zhlawi, H. J., Alhousani, T. N., Alzuraiqi, M. R., Al-Ja'afreh, M. M., Allouzy, S. K., ALjalamdeh, M., Mansour, T. M., Alamer, L. M., Issa, A., Younis, F., Hawari, F. I., Hayajneh, W. A., Obeidat, N. M., Ahram, M., Zhlawi, M. J., Alshaer, W., Al-Kasasbeh, M. M., Naffa, R. G., Ismail, M. A., Abdullah, M. S., Ismail, S. I., Obeidat, M., Cordero, A., Sin, D. D., Bosse, Y., Joubert, P., Hao, K., Nickle, D., Timens, W., van den Berge, M., Feng, Y., Mercader, J., Weiss, S. T., Karlson, E. W., Smoller, J. W., Murphy, S. N., Meigs, J. B., Woolley, A. E., Green, R. C., Mandla, R., Schroeder, P., Perez, E. F., Lee, S. 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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

Abstract

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

Abstract

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