870 results on '"Macarthur, Daniel G."'
Search Results
2. De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome
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Chen, Yuyang, Dawes, Ruebena, Kim, Hyung Chul, Ljungdahl, Alicia, Stenton, Sarah L., Walker, Susan, Lord, Jenny, Lemire, Gabrielle, Martin-Geary, Alexandra C., Ganesh, Vijay S., Ma, Jialan, Ellingford, Jamie M., Delage, Erwan, D’Souza, Elston N., Dong, Shan, Adams, David R., Allan, Kirsten, Bakshi, Madhura, Baldwin, Erin E., Berger, Seth I., Bernstein, Jonathan A., Bhatnagar, Ishita, Blair, Ed, Brown, Natasha J., Burrage, Lindsay C., Chapman, Kimberly, Coman, David J., Compton, Alison G., Cunningham, Chloe A., D’Souza, Precilla, Danecek, Petr, Délot, Emmanuèle C., Dias, Kerith-Rae, Elias, Ellen R., Elmslie, Frances, Evans, Care-Anne, Ewans, Lisa, Ezell, Kimberly, Fraser, Jamie L., Gallacher, Lyndon, Genetti, Casie A., Goriely, Anne, Grant, Christina L., Haack, Tobias, Higgs, Jenny E., Hinch, Anjali G., Hurles, Matthew E., Kuechler, Alma, Lachlan, Katherine L., Lalani, Seema R., Lecoquierre, François, Leitão, Elsa, Fevre, Anna Le, Leventer, Richard J., Liebelt, Jan E., Lindsay, Sarah, Lockhart, Paul J., Ma, Alan S., Macnamara, Ellen F., Mansour, Sahar, Maurer, Taylor M., Mendez, Hector R., Metcalfe, Kay, Montgomery, Stephen B., Moosajee, Mariya, Nassogne, Marie-Cécile, Neumann, Serena, O’Donoghue, Michael, O’Leary, Melanie, Palmer, Elizabeth E., Pattani, Nikhil, Phillips, John, Pitsava, Georgia, Pysar, Ryan, Rehm, Heidi L., Reuter, Chloe M., Revencu, Nicole, Riess, Angelika, Rius, Rocio, Rodan, Lance, Roscioli, Tony, Rosenfeld, Jill A., Sachdev, Rani, Shaw-Smith, Charles J., Simons, Cas, Sisodiya, Sanjay M., Snell, Penny, St Clair, Laura, Stark, Zornitza, Stewart, Helen S., Tan, Tiong Yang, Tan, Natalie B., Temple, Suzanna E. L., Thorburn, David R., Tifft, Cynthia J., Uebergang, Eloise, VanNoy, Grace E., Vasudevan, Pradeep, Vilain, Eric, Viskochil, David H., Wedd, Laura, Wheeler, Matthew T., White, Susan M., Wojcik, Monica, Wolfe, Lynne A., Wolfenson, Zoe, Wright, Caroline F., Xiao, Changrui, Zocche, David, Rubenstein, John L., Markenscoff-Papadimitriou, Eirene, Fica, Sebastian M., Baralle, Diana, Depienne, Christel, MacArthur, Daniel G., Howson, Joanna M. M., Sanders, Stephan J., O’Donnell-Luria, Anne, and Whiffin, Nicola
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- 2024
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3. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders
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Lee, Arthur S., Ayers, Lauren J., Kosicki, Michael, Chan, Wai-Man, Fozo, Lydia N., Pratt, Brandon M., Collins, Thomas E., Zhao, Boxun, Rose, Matthew F., Sanchis-Juan, Alba, Fu, Jack M., Wong, Isaac, Zhao, Xuefang, Tenney, Alan P., Lee, Cassia, Laricchia, Kristen M., Barry, Brenda J., Bradford, Victoria R., Jurgens, Julie A., England, Eleina M., Lek, Monkol, MacArthur, Daniel G., Lee, Eunjung Alice, Talkowski, Michael E., Brand, Harrison, Pennacchio, Len A., and Engle, Elizabeth C.
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- 2024
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4. Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes
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Wieder, Nechama, D’Souza, Elston N., Martin-Geary, Alexandra C., Lassen, Frederik H., Talbot-Martin, Jonathan, Fernandes, Maria, Chothani, Sonia P., Rackham, Owen J. L., Schafer, Sebastian, Aspden, Julie L., MacArthur, Daniel G., Davies, Robert W., and Whiffin, Nicola
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- 2024
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5. Sequencing and characterizing short tandem repeats in the human genome
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Tanudisastro, Hope A., Deveson, Ira W., Dashnow, Harriet, and MacArthur, Daniel G.
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- 2024
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6. Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases
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Farbehi, Nona, Neavin, Drew R., Cuomo, Anna S. E., Studer, Lorenz, MacArthur, Daniel G., and Powell, Joseph E.
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- 2024
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7. Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy
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Töpf, Ana, Cox, Dan, Zaharieva, Irina T., Di Leo, Valeria, Sarparanta, Jaakko, Jonson, Per Harald, Sealy, Ian M., Smolnikov, Andrei, White, Richard J., Vihola, Anna, Savarese, Marco, Merteroglu, Munise, Wali, Neha, Laricchia, Kristen M., Venturini, Cristina, Vroling, Bas, Stenton, Sarah L., Cummings, Beryl B., Harris, Elizabeth, Marini-Bettolo, Chiara, Diaz-Manera, Jordi, Henderson, Matt, Barresi, Rita, Duff, Jennifer, England, Eleina M., Patrick, Jane, Al-Husayni, Sundos, Biancalana, Valerie, Beggs, Alan H., Bodi, Istvan, Bommireddipalli, Shobhana, Bönnemann, Carsten G., Cairns, Anita, Chiew, Mei-Ting, Claeys, Kristl G., Cooper, Sandra T., Davis, Mark R., Donkervoort, Sandra, Erasmus, Corrie E., Fassad, Mahmoud R., Genetti, Casie A., Grosmann, Carla, Jungbluth, Heinz, Kamsteeg, Erik-Jan, Lornage, Xavière, Löscher, Wolfgang N., Malfatti, Edoardo, Manzur, Adnan, Martí, Pilar, Mongini, Tiziana E., Muelas, Nuria, Nishikawa, Atsuko, O’Donnell-Luria, Anne, Ogonuki, Narumi, O’Grady, Gina L., O’Heir, Emily, Paquay, Stéphanie, Phadke, Rahul, Pletcher, Beth A., Romero, Norma B., Schouten, Meyke, Shah, Snehal, Smuts, Izelle, Sznajer, Yves, Tasca, Giorgio, Taylor, Robert W., Tuite, Allysa, Van den Bergh, Peter, VanNoy, Grace, Voermans, Nicol C., Wanschitz, Julia V., Wraige, Elizabeth, Yoshimura, Kimihiko, Oates, Emily C., Nakagawa, Osamu, Nishino, Ichizo, Laporte, Jocelyn, Vilchez, Juan J., MacArthur, Daniel G., Sarkozy, Anna, Cordell, Heather J., Udd, Bjarne, Busch-Nentwich, Elisabeth M., Muntoni, Francesco, and Straub, Volker
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- 2024
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8. A genomic mutational constraint map using variation in 76,156 human genomes
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Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A., Vittal, Christopher, Gauthier, Laura D., Poterba, Timothy, Wilson, Michael W., Tarasova, Yekaterina, Phu, William, Grant, Riley, Yohannes, Mary T., Koenig, Zan, Farjoun, Yossi, Banks, Eric, Donnelly, Stacey, Gabriel, Stacey, Gupta, Namrata, Ferriera, Steven, Tolonen, Charlotte, Novod, Sam, Bergelson, Louis, Roazen, David, Ruano-Rubio, Valentin, Covarrubias, Miguel, Llanwarne, Christopher, Petrillo, Nikelle, Wade, Gordon, Jeandet, Thibault, Munshi, Ruchi, Tibbetts, Kathleen, O’Donnell-Luria, Anne, Solomonson, Matthew, Seed, Cotton, Martin, Alicia R., Talkowski, Michael E., Rehm, Heidi L., Daly, Mark J., Tiao, Grace, Neale, Benjamin M., MacArthur, Daniel G., and Karczewski, Konrad J.
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- 2024
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9. Inferring compound heterozygosity from large-scale exome sequencing data
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Guo, Michael H., Francioli, Laurent C., Stenton, Sarah L., Goodrich, Julia K., Watts, Nicholas A., Singer-Berk, Moriel, Groopman, Emily, Darnowsky, Philip W., Solomonson, Matthew, Baxter, Samantha, Tiao, Grace, Neale, Benjamin M., Hirschhorn, Joel N., Rehm, Heidi L., Daly, Mark J., O’Donnell-Luria, Anne, Karczewski, Konrad J., MacArthur, Daniel G., and Samocha, Kaitlin E.
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- 2024
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10. Single-cell genomics meets human genetics
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Cuomo, Anna S. E., Nathan, Aparna, Raychaudhuri, Soumya, MacArthur, Daniel G., and Powell, Joseph E.
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- 2023
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11. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease
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Lemire, Gabrielle, Sanchis-Juan, Alba, Russell, Kathryn, Baxter, Samantha, Chao, Katherine R., Singer-Berk, Moriel, Groopman, Emily, Wong, Isaac, England, Eleina, Goodrich, Julia, Pais, Lynn, Austin-Tse, Christina, DiTroia, Stephanie, O’Heir, Emily, Ganesh, Vijay S., Wojcik, Monica H., Evangelista, Emily, Snow, Hana, Osei-Owusu, Ikeoluwa, Fu, Jack, Singh, Mugdha, Mostovoy, Yulia, Huang, Steve, Garimella, Kiran, Kirkham, Samantha L., Neil, Jennifer E., Shao, Diane D., Walsh, Christopher A., Argilli, Emanuela, Le, Carolyn, Sherr, Elliott H., Gleeson, Joseph G., Shril, Shirlee, Schneider, Ronen, Hildebrandt, Friedhelm, Sankaran, Vijay G., Madden, Jill A., Genetti, Casie A., Beggs, Alan H., Agrawal, Pankaj B., Bujakowska, Kinga M., Place, Emily, Pierce, Eric A., Donkervoort, Sandra, Bönnemann, Carsten G., Gallacher, Lyndon, Stark, Zornitza, Tan, Tiong Yang, White, Susan M., Töpf, Ana, Straub, Volker, Fleming, Mark D., Pollak, Martin R., Õunap, Katrin, Pajusalu, Sander, Donald, Kirsten A., Bruwer, Zandre, Ravenscroft, Gianina, Laing, Nigel G., MacArthur, Daniel G., Rehm, Heidi L., Talkowski, Michael E., Brand, Harrison, and O’Donnell-Luria, Anne
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- 2024
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12. Variant interpretation using population databases: lessons from gnomAD
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Gudmundsson, Sanna, Singer-Berk, Moriel, Watts, Nicholas A., Phu, William, Goodrich, Julia K., Solomonson, Matthew, Consortium, Genome Aggregation Database, Rehm, Heidi L., MacArthur, Daniel G., and ODonnell-Luria, Anne
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Quantitative Biology - Genomics - Abstract
Reference population databases are an essential tool in variant and gene interpretation. Their use guides the identification of pathogenic variants amidst the sea of benign variation present in every human genome, and supports the discovery of new disease-gene relationships. The Genome Aggregation Database (gnomAD) is currently the largest and most widely used publicly available collection of population variation from harmonized sequencing data. The data is available through the online gnomAD browser (https://gnomad.broadinstitute.org/) that enables rapid and intuitive variant analysis. This review provides guidance on the content of the gnomAD browser, and its usage for variant and gene interpretation. We introduce key features including allele frequency, per-base expression levels, constraint scores, and variant co-occurrence, alongside guidance on how to use these in analysis, with a focus on the interpretation of candidate variants and novel genes in rare disease., Comment: Version 3: Includes updates to mirror the latest features and layouts available on the gnomAD browser and general improvements to text and figures (clarifications, typos, additional references etc.) as well as the addition of Table S1, S2, Figure S1, S2 and S5
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- 2021
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13. Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders
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Abarca-Barriga, Hugo, Al-Haddad, Christiane, Berman, Jeffrey L., Bothun, Erick D., Capasso, Jenina, Chacon-Camacho, Oscar Francisco, Chang, Lan, Christiansen, Stephen P., Ciccarelli, Maria Laura, Cordonnier, Monique, Cox, Gerald F., Curry, Cynthia J., Dagi, Linda R., Lee Dahm, Thomas, David, Karen L., Davitt, Bradley V., De Berardinis, Teresa, Demer, Joseph L., Désir, Julie, D’Esposito, Fabiana, Drack, Arlene V., Eggenberger, Eric, Elder, James E., Elliott, Alexandra T., Epley, K. David, Feldman, Hagit Baris, Ferreira, Carlos R., Flaherty, Maree P., Fulton, Anne B., Gerth-Kahlert, Christina, Gottlob, Irene, Grill, Stephen, Halliday, Dorothy J., Hanisch, Frank, Hay, Eleanor, Heidary, Gena, Holder, Christopher, Horton, Jonathan C., Iannaccone, Alessandro, Isenberg, Sherwin J., Johnston, Suzanne C., Kahana, Alon, Katowitz, James A., Kazlas, Melanie, Kerr, Natalie C., Kimonis, Virginia, Ko, Melissa W., Koc, Feray, Larsen, Dorte Ancher, Lay-Son, Guillermo, Ledoux, Danielle M., Levin, Alex V., Levy, Richard L., Lyons, Christopher J., Mackey, David A., Magli, Adriano, Mantagos, Iason S., Marti, Candice, Maystadt, Isabelle, McKenzie, Fiona, Menezes, Manoj P., Mikail, Claudia N., Miller, David T., Miller, Kathryn Bisceglia, Mills, Monte D., Miyana, Kaori, Moller, H.U., Mullineaux, Lisa, Nishimura, Julie K., Noble, A. Gwendolyn, Pandey, Pramod Kumar, Pavone, Piero, Penzien, Johann, Petersen, Robert, Phalen, James A., Poduri, Annapurna, Polo, Claudia R., Prasov, Lev, Ramos, Feliciano J., Ramos-Caceres, Maria, Robb, Richard M., Rossillion, Béatrice, Sahin, Mustafa, Singer, Harvey S., Smith, Lois E.H., Sorkin, Jeffrey A., Soul, Janet S., Staffieri, Sandra E., Stalker, Heather J., Stasheff, Steven F., Strassberg, Sonya, Strominger, Mitchell B., Taranath, Deepa Ajay, Thomas, Ioan Talfryn, Traboulsi, Elias I., Ugrin, Maria Cristina, VanderVeen, Deborah K., Vincent, Andrea L., Vogel G, Marlene C., Wabbels, Bettina, Wong, Agnes M.F., Woods, C. Geoffrey, Wu, Carolyn, Yang, Edward, Yeung, Alison, Young, Terri L., Zenteno, Juan C., Zubcov-Iwantscheff, Alexandra A., Zwaan, Johan, Jurgens, Julie A., Barry, Brenda J., Chan, Wai-Man, MacKinnon, Sarah, Whitman, Mary C., Matos Ruiz, Paola M., Pratt, Brandon M., England, Eleina M., Pais, Lynn, Lemire, Gabrielle, Groopman, Emily, Glaze, Carmen, Russell, Kathryn A., Singer-Berk, Moriel, Di Gioia, Silvio Alessandro, Lee, Arthur S., Andrews, Caroline, Shaaban, Sherin, Wirth, Megan M., Bekele, Sarah, Toffoloni, Melissa, Bradford, Victoria R., Foster, Emma E., Berube, Lindsay, Rivera-Quiles, Cristina, Mensching, Fiona M., Sanchis-Juan, Alba, Fu, Jack M., Wong, Isaac, Zhao, Xuefang, Wilson, Michael W., Weisburd, Ben, Lek, Monkol, Brand, Harrison, Talkowski, Michael E., MacArthur, Daniel G., O’Donnell-Luria, Anne, Robson, Caroline D., Hunter, David G., and Engle, Elizabeth C.
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- 2024
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14. Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes
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Chen, Siwei, Francioli, Laurent C., Goodrich, Julia K., Collins, Ryan L., Kanai, Masahiro, Wang, Qingbo, Alföldi, Jessica, Watts, Nicholas A., Vittal, Christopher, Gauthier, Laura D., Poterba, Timothy, Wilson, Michael W., Tarasova, Yekaterina, Phu, William, Grant, Riley, Yohannes, Mary T., Koenig, Zan, Farjoun, Yossi, Banks, Eric, Donnelly, Stacey, Gabriel, Stacey, Gupta, Namrata, Ferriera, Steven, Tolonen, Charlotte, Novod, Sam, Bergelson, Louis, Roazen, David, Ruano-Rubio, Valentin, Covarrubias, Miguel, Llanwarne, Christopher, Petrillo, Nikelle, Wade, Gordon, Jeandet, Thibault, Munshi, Ruchi, Tibbetts, Kathleen, O’Donnell-Luria, Anne, Solomonson, Matthew, Seed, Cotton, Martin, Alicia R., Talkowski, Michael E., Rehm, Heidi L., Daly, Mark J., Tiao, Grace, Neale, Benjamin M., MacArthur, Daniel G., and Karczewski, Konrad J.
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- 2024
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15. Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data
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Singer-Berk, Moriel, Gudmundsson, Sanna, Baxter, Samantha, Seaby, Eleanor G., England, Eleina, Wood, Jordan C., Son, Rachel G., Watts, Nicholas A., Karczewski, Konrad J., Harrison, Steven M., MacArthur, Daniel G., Rehm, Heidi L., and O’Donnell-Luria, Anne
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- 2023
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16. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings
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McGurk, Kathryn A., Zhang, Xiaolei, Theotokis, Pantazis, Thomson, Kate, Harper, Andrew, Buchan, Rachel J., Mazaika, Erica, Ormondroyd, Elizabeth, Wright, William T., Macaya, Daniela, Pua, Chee Jian, Funke, Birgit, MacArthur, Daniel G., Prasad, Sanjay K., Cook, Stuart A., Allouba, Mona, Aguib, Yasmine, Yacoub, Magdi H., O'Regan, Declan P., Barton, Paul J.R., Watkins, Hugh, Bottolo, Leonardo, and Ware, James S.
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- 2023
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17. Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies
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Lowther, Chelsea, Valkanas, Elise, Giordano, Jessica L., Wang, Harold Z., Currall, Benjamin B., O’Keefe, Kathryn, Pierce-Hoffman, Emma, Kurtas, Nehir E., Whelan, Christopher W., Hao, Stephanie P., Weisburd, Ben, Jalili, Vahid, Fu, Jack, Wong, Isaac, Collins, Ryan L., Zhao, Xuefang, Austin-Tse, Christina A., Evangelista, Emily, Lemire, Gabrielle, Aggarwal, Vimla S., Lucente, Diane, Gauthier, Laura D., Tolonen, Charlotte, Sahakian, Nareh, Stevens, Christine, An, Joon-Yong, Dong, Shan, Norton, Mary E., MacKenzie, Tippi C., Devlin, Bernie, Gilmore, Kelly, Powell, Bradford C., Brandt, Alicia, Vetrini, Francesco, DiVito, Michelle, Sanders, Stephan J., MacArthur, Daniel G., Hodge, Jennelle C., O'Donnell-Luria, Anne, Rehm, Heidi L., Vora, Neeta L., Levy, Brynn, Brand, Harrison, Wapner, Ronald J., and Talkowski, Michael E.
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- 2023
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18. A structural variation reference for medical and population genetics
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Collins, Ryan L, Brand, Harrison, Karczewski, Konrad J, Zhao, Xuefang, Alföldi, Jessica, Francioli, Laurent C, Khera, Amit V, Lowther, Chelsea, Gauthier, Laura D, Wang, Harold, Watts, Nicholas A, Solomonson, Matthew, O’Donnell-Luria, Anne, Baumann, Alexander, Munshi, Ruchi, Walker, Mark, Whelan, Christopher W, Huang, Yongqing, Brookings, Ted, Sharpe, Ted, Stone, Matthew R, Valkanas, Elise, Fu, Jack, Tiao, Grace, Laricchia, Kristen M, Ruano-Rubio, Valentin, Stevens, Christine, Gupta, Namrata, Cusick, Caroline, Margolin, Lauren, Taylor, Kent D, Lin, Henry J, Rich, Stephen S, Post, Wendy S, Chen, Yii-Der Ida, Rotter, Jerome I, Nusbaum, Chad, Philippakis, Anthony, Lander, Eric, Gabriel, Stacey, Neale, Benjamin M, Kathiresan, Sekar, Daly, Mark J, Banks, Eric, MacArthur, Daniel G, and Talkowski, Michael E
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Biotechnology ,Generic health relevance ,Disease ,Female ,Genetic Testing ,Genetic Variation ,Genetics ,Medical ,Genetics ,Population ,Genome ,Human ,Genotyping Techniques ,Humans ,Male ,Middle Aged ,Mutation ,Polymorphism ,Single Nucleotide ,Racial Groups ,Reference Standards ,Selection ,Genetic ,Whole Genome Sequencing ,Genome Aggregation Database Production Team ,Genome Aggregation Database Consortium ,General Science & Technology - Abstract
Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.
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- 2020
19. Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer
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Carrot-Zhang, Jian, Chambwe, Nyasha, Damrauer, Jeffrey S, Knijnenburg, Theo A, Robertson, A Gordon, Yau, Christina, Zhou, Wanding, Berger, Ashton C, Huang, Kuan-lin, Newberg, Justin Y, Mashl, R Jay, Romanel, Alessandro, Sayaman, Rosalyn W, Demichelis, Francesca, Felau, Ina, Frampton, Garrett M, Han, Seunghun, Hoadley, Katherine A, Kemal, Anab, Laird, Peter W, Lazar, Alexander J, Le, Xiuning, Oak, Ninad, Shen, Hui, Wong, Christopher K, Zenklusen, Jean C, Ziv, Elad, Network, Cancer Genome Atlas Analysis, Aguet, Francois, Ding, Li, Demchok, John A, Mensah, Michael KA, Caesar-Johnson, Samantha, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Alfoldi, Jessica, Karczewski, Konrad J, MacArthur, Daniel G, Meyerson, Matthew, Benz, Christopher, Stuart, Joshua M, Cherniack, Andrew D, and Beroukhim, Rameen
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Urologic Diseases ,Human Genome ,Cancer Genomics ,Biotechnology ,DNA Methylation ,DNA-Binding Proteins ,Ethnicity ,F-Box-WD Repeat-Containing Protein 7 ,Gene Expression Regulation ,Neoplastic ,Genetic Predisposition to Disease ,Genetics ,Population ,Genome ,Human ,Genomics ,High-Throughput Nucleotide Sequencing ,Humans ,MicroRNAs ,Mutation ,Neoplasm Proteins ,Neoplasms ,Transcription Factors ,Von Hippel-Lindau Tumor Suppressor Protein ,Cancer Genome Atlas Analysis Network ,TCGA ,admixture ,ancestry ,cancer ,eQTL ,genomics ,mRNA ,methylation ,miRNA ,mutation ,Neurosciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.
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- 2020
20. Transcriptome variation in human tissues revealed by long-read sequencing
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Glinos, Dafni A., Garborcauskas, Garrett, Hoffman, Paul, Ehsan, Nava, Jiang, Lihua, Gokden, Alper, Dai, Xiaoguang, Aguet, François, Brown, Kathleen L., Garimella, Kiran, Bowers, Tera, Costello, Maura, Ardlie, Kristin, Jian, Ruiqi, Tucker, Nathan R., Ellinor, Patrick T., Harrington, Eoghan D., Tang, Hua, Snyder, Michael, Juul, Sissel, Mohammadi, Pejman, MacArthur, Daniel G., Lappalainen, Tuuli, and Cummings, Beryl B.
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- 2022
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21. Systematic single-variant and gene-based association testing of thousands of phenotypes in 394,841 UK Biobank exomes
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Karczewski, Konrad J., Solomonson, Matthew, Chao, Katherine R., Goodrich, Julia K., Tiao, Grace, Lu, Wenhan, Riley-Gillis, Bridget M., Tsai, Ellen A., Kim, Hye In, Zheng, Xiuwen, Rahimov, Fedik, Esmaeeli, Sahar, Grundstad, A. Jason, Reppell, Mark, Waring, Jeff, Jacob, Howard, Sexton, David, Bronson, Paola G., Chen, Xing, Hu, Xinli, Goldstein, Jacqueline I., King, Daniel, Vittal, Christopher, Poterba, Timothy, Palmer, Duncan S., Churchhouse, Claire, Howrigan, Daniel P., Zhou, Wei, Watts, Nicholas A., Nguyen, Kevin, Nguyen, Huy, Mason, Cara, Farnham, Christopher, Tolonen, Charlotte, Gauthier, Laura D., Gupta, Namrata, MacArthur, Daniel G., Rehm, Heidi L., Seed, Cotton, Philippakis, Anthony A., Daly, Mark J., Davis, J. Wade, Runz, Heiko, Miller, Melissa R., and Neale, Benjamin M.
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- 2022
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22. Centers for Mendelian Genomics: A decade of facilitating gene discovery
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Adams, Marcia, Aguet, François, Akay, Gulsen, Anderson, Peter, Antonescu, Corina, Arachchi, Harindra M., Atik, Mehmed M., Austin-Tse, Christina A., Babb, Larry, Bacus, Tamara J., Bahrambeigi, Vahid, Balasubramanian, Suganthi, Bayram, Yavuz, Beaudet, Arthur L., Beck, Christine R., Belmont, John W., Below, Jennifer E., Bilguvar, Kaya, Boehm, Corinne D., Boerwinkle, Eric, Boone, Philip M., Bowne, Sara J., Brand, Harrison, Buckingham, Kati J., Byrne, Alicia B., Calame, Daniel, Campbell, Ian M., Cao, Xiaolong, Carvalho, Claudia, Chander, Varuna, Chang, Jaime, Chao, Katherine R., Chinn, Ivan K., Clarke, Declan, Collins, Ryan L., Cummings, Beryl, Dardas, Zain, Dawood, Moez, Delano, Kayla, DiTroia, Stephanie P., Doddapaneni, Harshavardhan, Du, Haowei, Du, Renqian, Duan, Ruizhi, Eldomery, Mohammad, Eng, Christine M., England, Eleina, Evangelista, Emily, Everett, Selin, Fatih, Jawid, Felsenfeld, Adam, Francioli, Laurent C., Frazar, Christian D., Fu, Jack, Gamarra, Emmanuel, Gambin, Tomasz, Gan, Weiniu, Gandhi, Mira, Ganesh, Vijay S., Garimella, Kiran V., Gauthier, Laura D., Giroux, Danielle, Gonzaga-Jauregui, Claudia, Goodrich, Julia K., Gordon, William W., Griffith, Sean, Grochowski, Christopher M., Gu, Shen, Gudmundsson, Sanna, Hall, Stacey J., Hansen, Adam, Harel, Tamar, Harmanci, Arif O., Herman, Isabella, Hetrick, Kurt, Hijazi, Hadia, Horike-Pyne, Martha, Hsu, Elvin, Hu, Jianhong, Huang, Yongqing, Hurless, Jameson R., Jahl, Steve, Jarvik, Gail P., Jiang, Yunyun, Johanson, Eric, Jolly, Angad, Karaca, Ender, Khayat, Michael, Knight, James, Kolar, J. Thomas, Kumar, Sushant, Lalani, Seema, Laricchia, Kristen M., Larkin, Kathryn E., Leal, Suzanne M., Lemire, Gabrielle, Lewis, Richard A., Li, He, Ling, Hua, Lipson, Rachel B., Liu, Pengfei, Lovgren, Alysia Kern, López-Giráldez, Francesc, MacMillan, Melissa P., Mangilog, Brian E., Mano, Stacy, Marafi, Dana, Marosy, Beth, Marshall, Jamie L., Martin, Renan, Marvin, Colby T., Mawhinney, Michelle, McGee, Sean, McGoldrick, Daniel J., Mehaffey, Michelle, Mekonnen, Betselote, Meng, Xiaolu, Mitani, Tadahiro, Miyake, Christina Y., Mohr, David, Morris, Shaine, Mullen, Thomas E., Murdock, David R., Murugan, Mullai, Muzny, Donna M., Myers, Ben, Neira, Juanita, Nguyen, Kevin K., Nielsen, Patrick M., Nudelman, Natalie, O’Heir, Emily, O’Leary, Melanie C., Ongaco, Chrissie, Orange, Jordan, Osei-Owusu, Ikeoluwa A., Paine, Ingrid S., Pais, Lynn S., Paschall, Justin, Patterson, Karynne, Pehlivan, Davut, Pelle, Benjamin, Penney, Samantha, Perez de Acha Chavez, Jorge, Pierce-Hoffman, Emma, Poli, Cecilia M., Punetha, Jaya, Radhakrishnan, Aparna, Richardson, Matthew A., Rodrigues, Eliete, Roote, Gwendolin T., Rosenfeld, Jill A., Ryke, Erica L., Sabo, Aniko, Sanchez, Alice, Schrauwen, Isabelle, Scott, Daryl A., Sedlazeck, Fritz, Serrano, Jillian, Shaw, Chad A., Shelford, Tameka, Shively, Kathryn M., Singer-Berk, Moriel, Smith, Joshua D., Snow, Hana, Snyder, Grace, Solomonson, Matthew, Son, Rachel G., Song, Xiaofei, Stankiewicz, Pawel, Stephan, Taylorlyn, Sutton, V. Reid, Sveden, Abigail, Sánchez, Diana Cornejo, Tackett, Monica, Talkowski, Michael, Threlkeld, Machiko S., Tiao, Grace, Udler, Miriam S., Vail, Laura, Valivullah, Zaheer, Valkanas, Elise, VanNoy, Grace E., Wang, Qingbo S., Wang, Gao, Wang, Lu, Wangler, Michael F., Watts, Nicholas A., Weisburd, Ben, Weiss, Jeffrey M., Wheeler, Marsha M., White, Janson J., Williamson, Clara E., Wilson, Michael W., Wiszniewski, Wojciech, Withers, Marjorie A., Witmer, Dane, Witzgall, Lauren, Wohler, Elizabeth, Wojcik, Monica H., Wong, Isaac, Wood, Jordan C., Wu, Nan, Xing, Jinchuan, Yang, Yaping, Yi, Qian, Yuan, Bo, Zeiger, Jordan E., Zhang, Chaofan, Zhang, Peng, Zhang, Yan, Zhang, Xiaohong, Zhang, Yeting, Zhang, Shifa, Zoghbi, Huda, van den Veyver, Igna, Baxter, Samantha M., Posey, Jennifer E., Lake, Nicole J., Sobreira, Nara, Chong, Jessica X., Buyske, Steven, Blue, Elizabeth E., Chadwick, Lisa H., Coban-Akdemir, Zeynep H., Doheny, Kimberly F., Davis, Colleen P., Lek, Monkol, Wellington, Christopher, Jhangiani, Shalini N., Gerstein, Mark, Gibbs, Richard A., Lifton, Richard P., MacArthur, Daniel G., Matise, Tara C., Lupski, James R., Valle, David, Bamshad, Michael J., Hamosh, Ada, Mane, Shrikant, Nickerson, Deborah A., Rehm, Heidi L., and O’Donnell-Luria, Anne
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- 2022
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23. Whole-genome analysis of human embryonic stem cells enables rational line selection based on genetic variation
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Merkle, Florian T., Ghosh, Sulagna, Genovese, Giulio, Handsaker, Robert E., Kashin, Seva, Meyer, Daniel, Karczewski, Konrad J., O’Dushlaine, Colm, Pato, Carlos, Pato, Michele, MacArthur, Daniel G., McCarroll, Steven A., and Eggan, Kevin
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- 2022
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24. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica.
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Estrada, Karol, Whelan, Christopher W, Zhao, Fengmei, Bronson, Paola, Handsaker, Robert E, Sun, Chao, Carulli, John P, Harris, Tim, Ransohoff, Richard M, McCarroll, Steven A, Day-Williams, Aaron G, Greenberg, Benjamin M, and MacArthur, Daniel G
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Humans ,Neuromyelitis Optica ,Genetic Predisposition to Disease ,Immunoglobulin G ,Risk Factors ,Major Histocompatibility Complex ,Haplotypes ,Polymorphism ,Single Nucleotide ,Adult ,Middle Aged ,Female ,Male ,Aquaporin 4 ,DNA Copy Number Variations ,Whole Genome Sequencing ,Polymorphism ,Single Nucleotide - Abstract
Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.
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- 2018
25. Quantitative analysis of population-scale family trees with millions of relatives
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Kaplanis, Joanna, Gordon, Assaf, Shor, Tal, Weissbrod, Omer, Geiger, Dan, Wahl, Mary, Gershovits, Michael, Markus, Barak, Sheikh, Mona, Gymrek, Melissa, Bhatia, Gaurav, MacArthur, Daniel G, Price, Alkes L, and Erlich, Yaniv
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Genetics ,Generic health relevance ,Datasets as Topic ,Family ,Genealogy and Heraldry ,Humans ,Longevity ,Models ,Genetic ,Pedigree ,Population ,General Science & Technology - Abstract
Family trees have vast applications in fields as diverse as genetics, anthropology, and economics. However, the collection of extended family trees is tedious and usually relies on resources with limited geographical scope and complex data usage restrictions. We collected 86 million profiles from publicly available online data shared by genealogy enthusiasts. After extensive cleaning and validation, we obtained population-scale family trees, including a single pedigree of 13 million individuals. We leveraged the data to partition the genetic architecture of human longevity and to provide insights into the geographical dispersion of families. We also report a simple digital procedure to overlay other data sets with our resource.
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- 2018
26. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease
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Anand, Shankara, Gabriel, Stacey, Getz, Gad A., Graubert, Aaron, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Li, Xiao, MacArthur, Daniel G., Meier, Samuel R., Nedzel, Jared L., Nguyen, Duyen T., Segrè, Ayellet V., Todres, Ellen, Balliu, Brunilda, Bonazzola, Rodrigo, Brown, Andrew, Conrad, Donald F., Cotter, Daniel J., Cox, Nancy, Das, Sayantan, Dermitzakis, Emmanouil T., Einson, Jonah, Engelhardt, Barbara E., Eskin, Eleazar, Flynn, Elise D., Fresard, Laure, Gamazon, Eric R., Garrido-Martín, Diego, Gay, Nicole R., Guigó, Roderic, Hamel, Andrew R., He, Yuan, Hoffman, Paul J., Hormozdiari, Farhad, Hou, Lei, Jo, Brian, Kasela, Silva, Kashin, Seva, Kellis, Manolis, Kwong, Alan, Li, Xin, Liang, Yanyu, Mangul, Serghei, Mohammadi, Pejman, Muñoz-Aguirre, Manuel, Nobel, Andrew B., Oliva, Meritxell, Park, Yongjin, Parsana, Princy, Reverter, Ferran, Rouhana, John M., Sabatti, Chiara, Saha, Ashis, Stephens, Matthew, Stranger, Barbara E., Teran, Nicole A., Viñuela, Ana, Wang, Gao, Wright, Fred, Wucher, Valentin, Zou, Yuxin, Ferreira, Pedro G., Li, Gen, Melé, Marta, Yeger-Lotem, Esti, Bradbury, Debra, Krubit, Tanya, McLean, Jeffrey A., Qi, Liqun, Robinson, Karna, Roche, Nancy V., Smith, Anna M., Tabor, David E., Undale, Anita, Bridge, Jason, Brigham, Lori E., Foster, Barbara A., Gillard, Bryan M., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Karasik, Ellen, Kopen, Gene, Leinweber, William F., McDonald, Alisa, Moser, Michael T., Myer, Kevin, Ramsey, Kimberley D., Roe, Brian, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Jewell, Scott D., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Barcus, Mary E., Branton, Philip A., Sobin, Leslie, Barker, Laura K., Gardiner, Heather M., Mosavel, Maghboeba, Siminoff, Laura A., Flicek, Paul, Haeussler, Maximilian, Juettemann, Thomas, Kent, W. James, Lee, Christopher M., Powell, Conner C., Rosenbloom, Kate R., Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Abell, Nathan S., Akey, Joshua, Chen, Lin, Demanelis, Kathryn, Doherty, Jennifer A., Feinberg, Andrew P., Hansen, Kasper D., Hickey, Peter F., Jasmine, Farzana, Jiang, Lihua, Kaul, Rajinder, Kibriya, Muhammad G., Li, Jin Billy, Li, Qin, Lin, Shin, Linder, Sandra E., Pierce, Brandon L., Rizzardi, Lindsay F., Skol, Andrew D., Smith, Kevin S., Snyder, Michael, Stamatoyannopoulos, John, Tang, Hua, Wang, Meng, Carithers, Latarsha J., Guan, Ping, Koester, Susan E., Little, A. Roger, Moore, Helen M., Nierras, Concepcion R., Rao, Abhi K., Vaught, Jimmie B., Volpi, Simona, de Goede, Olivia M., Nachun, Daniel C., Ferraro, Nicole M., Gloudemans, Michael J., Rao, Abhiram S., Smail, Craig, Eulalio, Tiffany Y., Aguet, François, Ng, Bernard, Xu, Jishu, Barbeira, Alvaro N., Castel, Stephane E., Kim-Hellmuth, Sarah, Park, YoSon, Scott, Alexandra J., Strober, Benjamin J., Brown, Christopher D., Wen, Xiaoquan, Hall, Ira M., Battle, Alexis, Lappalainen, Tuuli, Im, Hae Kyung, Ardlie, Kristin G., Mostafavi, Sara, Quertermous, Thomas, Kirkegaard, Karla, and Montgomery, Stephen B.
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- 2021
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27. Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia
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Muir, Alison M., Gardner, Jennifer F., van Jaarsveld, Richard H., de Lange, Iris M., van der Smagt, Jasper J., Wilson, Golder N., Dubbs, Holly, Goldberg, Ethan M., Zitano, Lia, Bupp, Caleb, Martinez, Jose, Srour, Myriam, Accogli, Andrea, Alhakeem, Afnan, Meltzer, Meira, Gropman, Andrea, Brewer, Carole, Caswell, Richard C., Montgomery, Tara, McKenna, Caoimhe, McKee, Shane, Powell, Corinna, Vasudevan, Pradeep C., Brady, Angela F., Joss, Shelagh, Tysoe, Carolyn, Noh, Grace, Tarnopolsky, Mark, Brady, Lauren, Zafar, Muhammad, Schrier Vergano, Samantha A., Murray, Brianna, Sawyer, Lindsey, Hainline, Bryan E., Sapp, Katherine, DeMarzo, Danielle, Huismann, Darcy J., Wentzensen, Ingrid M., Schnur, Rhonda E., Monaghan, Kristin G., Juusola, Jane, Rhodes, Lindsay, Dobyns, William B., Lecoquierre, Francois, Goldenberg, Alice, Polster, Tilman, Axer-Schaefer, Susanne, Platzer, Konrad, Klöckner, Chiara, Hoffman, Trevor L., MacArthur, Daniel G., O’Leary, Melanie C., VanNoy, Grace E., England, Eleina, Varghese, Vinod C., and Mefford, Heather C.
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- 2021
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28. Correction: Corrigendum: High-throughput discovery of novel developmental phenotypes
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Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie Helmut Fuchs, Sarah M, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Nutter, Susan Newbigging Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, and Murray, Maja Bućan Stephen A
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International Mouse Phenotyping Consortium ,General Science & Technology - Abstract
This corrects the article DOI: 10.1038/nature19356.
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- 2017
29. Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis
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Yang, Fan, Wang, Jiebiao, Consortium, The GTEx, Pierce, Brandon L, Chen, Lin S, Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Im, Hae Kyung, Jo, Brian, Kang, Eun Yong, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, and Wang, Gao
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Biotechnology ,Human Genome ,2.1 Biological and endogenous factors ,Generic health relevance ,Good Health and Well Being ,Databases ,Genetic ,Gene Expression Profiling ,Gene Expression Regulation ,Gene Regulatory Networks ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genomics ,Humans ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Selection ,Genetic ,Tissue Distribution ,GTEx Consortium ,Medical and Health Sciences ,Bioinformatics - Abstract
The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is "mediation" by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are "cis-mediators" of trans-eQTLs, including those "cis-hubs" involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types.
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- 2017
30. Co-expression networks reveal the tissue-specific regulation of transcription and splicing
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Saha, Ashis, Kim, Yungil, Gewirtz, Ariel DH, Jo, Brian, Gao, Chuan, McDowell, Ian C, Consortium, The GTEx, Engelhardt, Barbara E, Battle, Alexis, Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Im, Hae Kyung, Kang, Eun Yong, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, and Sul, Jae Hoon
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Biotechnology ,Human Genome ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Generic health relevance ,Bayes Theorem ,Databases ,Genetic ,Gene Expression Profiling ,Gene Expression Regulation ,Gene Regulatory Networks ,Genotyping Techniques ,Humans ,Organ Specificity ,Polymorphism ,Single Nucleotide ,RNA Splicing ,Sequence Analysis ,RNA ,GTEx Consortium ,Medical and Health Sciences ,Bioinformatics - Abstract
Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.
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- 2017
31. Dynamic landscape and regulation of RNA editing in mammals
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Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A, Xi, Hualin S, Yeger-Lotem, Esti, and Zappala, Zachary
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Adenosine Deaminase ,Animals ,Female ,Genotype ,HEK293 Cells ,Humans ,Male ,Mice ,Muscles ,Nuclear Proteins ,Organ Specificity ,Primates ,Proteolysis ,RNA Editing ,RNA-Binding Proteins ,Spatio-Temporal Analysis ,Species Specificity ,Transcriptome ,GTEx Consortium ,Laboratory ,Data Analysis &Coordinating Center (LDACC)—Analysis Working Group ,Statistical Methods groups—Analysis Working Group ,Enhancing GTEx (eGTEx) groups ,NIH Common Fund ,NIH/NCI ,NIH/NHGRI ,NIH/NIMH ,NIH/NIDA ,Biospecimen Collection Source Site—NDRI ,Biospecimen Collection Source Site—RPCI ,Biospecimen Core Resource—VARI ,Brain Bank Repository—University of Miami Brain Endowment Bank ,Leidos Biomedical—Project Management ,ELSI Study ,Genome Browser Data Integration &Visualization—EBI ,Genome Browser Data Integration &Visualization—UCSC Genomics Institute ,University of California Santa Cruz ,General Science & Technology - Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.
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- 2017
32. Landscape of X chromosome inactivation across human tissues
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Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A, Xi, Hualin S, Yeger-Lotem, Esti, and Zappala, Zachary
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Genetics ,Clinical Research ,Human Genome ,Generic health relevance ,Good Health and Well Being ,Chromosomes ,Human ,X ,Female ,Genes ,X-Linked ,Genome ,Human ,Genomics ,Humans ,Male ,Organ Specificity ,Phenotype ,Sequence Analysis ,RNA ,Single-Cell Analysis ,Transcriptome ,X Chromosome Inactivation ,GTEx Consortium ,Laboratory ,Data Analysis &Coordinating Center (LDACC)—Analysis Working Group ,Statistical Methods groups—Analysis Working Group ,Enhancing GTEx (eGTEx) groups ,NIH Common Fund ,NIH/NCI ,NIH/NHGRI ,NIH/NIMH ,NIH/NIDA ,Biospecimen Collection Source Site—NDRI ,Biospecimen Collection Source Site—RPCI ,Biospecimen Core Resource—VARI ,Brain Bank Repository—University of Miami Brain Endowment Bank ,Leidos Biomedical—Project Management ,ELSI Study ,Genome Browser Data Integration &Visualization—EBI ,Genome Browser Data Integration &Visualization—UCSC Genomics Institute ,University of California Santa Cruz ,General Science & Technology - Abstract
X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
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- 2017
33. The impact of rare variation on gene expression across tissues
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Aguet, François, Ardlie, Kristin G, Cummings, Beryl B, Gelfand, Ellen T, Getz, Gad, Hadley, Kane, Handsaker, Robert E, Huang, Katherine H, Kashin, Seva, Karczewski, Konrad J, Lek, Monkol, Li, Xiao, MacArthur, Daniel G, Nedzel, Jared L, Nguyen, Duyen T, Noble, Michael S, Segrè, Ayellet V, Trowbridge, Casandra A, Tukiainen, Taru, Abell, Nathan S, Balliu, Brunilda, Barshir, Ruth, Basha, Omer, Battle, Alexis, Bogu, Gireesh K, Brown, Andrew, Brown, Christopher D, Castel, Stephane E, Chen, Lin S, Chiang, Colby, Conrad, Donald F, Cox, Nancy J, Damani, Farhan N, Davis, Joe R, Delaneau, Olivier, Dermitzakis, Emmanouil T, Engelhardt, Barbara E, Eskin, Eleazar, Ferreira, Pedro G, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Guigo, Roderic, Hall, Ira M, Han, Buhm, He, Yuan, Hormozdiari, Farhad, Howald, Cedric, Kyung Im, Hae, Jo, Brian, Yong Kang, Eun, Kim, Yungil, Kim-Hellmuth, Sarah, Lappalainen, Tuuli, Li, Gen, Li, Xin, Liu, Boxiang, Mangul, Serghei, McCarthy, Mark I, McDowell, Ian C, Mohammadi, Pejman, Monlong, Jean, Montgomery, Stephen B, Muñoz-Aguirre, Manuel, Ndungu, Anne W, Nicolae, Dan L, Nobel, Andrew B, Oliva, Meritxell, Ongen, Halit, Palowitch, John J, Panousis, Nikolaos, Papasaikas, Panagiotis, Park, YoSon, Parsana, Princy, Payne, Anthony J, Peterson, Christine B, Quan, Jie, Reverter, Ferran, Sabatti, Chiara, Saha, Ashis, Sammeth, Michael, Scott, Alexandra J, Shabalin, Andrey A, Sodaei, Reza, Stephens, Matthew, Stranger, Barbara E, Strober, Benjamin J, Sul, Jae Hoon, Tsang, Emily K, Urbut, Sarah, van de Bunt, Martijn, Wang, Gao, Wen, Xiaoquan, Wright, Fred A, Xi, Hualin S, Yeger-Lotem, Esti, and Zappala, Zachary
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Bayes Theorem ,Female ,Gene Expression Profiling ,Genetic Variation ,Genome ,Human ,Genomics ,Genotype ,Humans ,Male ,Models ,Genetic ,Organ Specificity ,Sequence Analysis ,RNA ,GTEx Consortium ,Laboratory ,Data Analysis &Coordinating Center (LDACC)—Analysis Working Group ,Statistical Methods groups—Analysis Working Group ,Enhancing GTEx (eGTEx) groups ,NIH Common Fund ,NIH/NCI ,NIH/NHGRI ,NIH/NIMH ,NIH/NIDA ,Biospecimen Collection Source Site—NDRI ,Biospecimen Collection Source Site—RPCI ,Biospecimen Core Resource—VARI ,Brain Bank Repository—University of Miami Brain Endowment Bank ,Leidos Biomedical—Project Management ,ELSI Study ,Genome Browser Data Integration &Visualization—EBI ,Genome Browser Data Integration &Visualization—UCSC Genomics Institute ,University of California Santa Cruz ,General Science & Technology - Abstract
Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.
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- 2017
34. Genetic effects on gene expression across human tissues
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Aguet, François, Brown, Andrew A, Castel, Stephane E, Davis, Joe R, He, Yuan, Jo, Brian, Mohammadi, Pejman, Park, YoSon, Parsana, Princy, Segrè, Ayellet V, Strober, Benjamin J, Zappala, Zachary, Cummings, Beryl B, Gelfand, Ellen T, Hadley, Kane, Huang, Katherine H, Lek, Monkol, Li, Xiao, Nedzel, Jared L, Nguyen, Duyen Y, Noble, Michael S, Sullivan, Timothy J, Tukiainen, Taru, MacArthur, Daniel G, Getz, Gad, Addington, Anjene, Guan, Ping, Koester, Susan, Little, A Roger, Lockhart, Nicole C, Moore, Helen M, Rao, Abhi, Struewing, Jeffery P, Volpi, Simona, Brigham, Lori E, Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Kopen, Gene, Leinweber, William F, Lonsdale, John T, McDonald, Alisa, Mestichelli, Bernadette, Myer, Kevin, Roe, Bryan, Salvatore, Michael, Shad, Saboor, Thomas, Jeffrey A, Walters, Gary, Washington, Michael, Wheeler, Joseph, Bridge, Jason, Foster, Barbara A, Gillard, Bryan M, Karasik, Ellen, Kumar, Rachna, Miklos, Mark, Moser, Michael T, Jewell, Scott D, Montroy, Robert G, Rohrer, Daniel C, Valley, Dana, Mash, Deborah C, Davis, David A, Sobin, Leslie, Barcus, Mary E, Branton, Philip A, Abell, Nathan S, Balliu, Brunilda, Delaneau, Olivier, Frésard, Laure, Gamazon, Eric R, Garrido-Martín, Diego, Gewirtz, Ariel DH, Gliner, Genna, Gloudemans, Michael J, Han, Buhm, He, Amy Z, Hormozdiari, Farhad, Li, Xin, Liu, Boxiang, Kang, Eun Yong, McDowell, Ian C, Ongen, Halit, Palowitch, John J, Peterson, Christine B, Quon, Gerald, Ripke, Stephan, Saha, Ashis, Shabalin, Andrey A, Shimko, Tyler C, Sul, Jae Hoon, Teran, Nicole A, Tsang, Emily K, Zhang, Hailei, Zhou, Yi-Hui, Bustamante, Carlos D, Cox, Nancy J, and Guigó, Roderic
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Biotechnology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Generic health relevance ,Alleles ,Chromosomes ,Human ,Disease ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Genetic Variation ,Genome ,Human ,Genotype ,Humans ,Male ,Organ Specificity ,Quantitative Trait Loci ,GTEx Consortium ,Laboratory ,Data Analysis &Coordinating Center (LDACC)—Analysis Working Group ,Statistical Methods groups—Analysis Working Group ,Enhancing GTEx (eGTEx) groups ,NIH Common Fund ,NIH/NCI ,NIH/NHGRI ,NIH/NIMH ,NIH/NIDA ,Biospecimen Collection Source Site—NDRI ,Biospecimen Collection Source Site—RPCI ,Biospecimen Core Resource—VARI ,Brain Bank Repository—University of Miami Brain Endowment Bank ,Leidos Biomedical—Project Management ,ELSI Study ,Genome Browser Data Integration &Visualization—EBI ,Genome Browser Data Integration &Visualization—UCSC Genomics Institute ,University of California Santa Cruz ,Lead analysts: ,Laboratory ,Data Analysis &Coordinating Center (LDACC): ,NIH program management: ,Biospecimen collection: ,Pathology: ,eQTL manuscript working group: ,General Science & Technology - Abstract
Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
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- 2017
35. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.
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Willems, Sara M, Wright, Daniel J, Day, Felix R, Trajanoska, Katerina, Joshi, Peter K, Morris, John A, Matteini, Amy M, Garton, Fleur C, Grarup, Niels, Oskolkov, Nikolay, Thalamuthu, Anbupalam, Mangino, Massimo, Liu, Jun, Demirkan, Ayse, Lek, Monkol, Xu, Liwen, Wang, Guan, Oldmeadow, Christopher, Gaulton, Kyle J, Lotta, Luca A, Miyamoto-Mikami, Eri, Rivas, Manuel A, White, Tom, Loh, Po-Ru, Aadahl, Mette, Amin, Najaf, Attia, John R, Austin, Krista, Benyamin, Beben, Brage, Søren, Cheng, Yu-Ching, Cięszczyk, Paweł, Derave, Wim, Eriksson, Karl-Fredrik, Eynon, Nir, Linneberg, Allan, Lucia, Alejandro, Massidda, Myosotis, Mitchell, Braxton D, Miyachi, Motohiko, Murakami, Haruka, Padmanabhan, Sandosh, Pandey, Ashutosh, Papadimitriou, Ioannis, Rajpal, Deepak K, Sale, Craig, Schnurr, Theresia M, Sessa, Francesco, Shrine, Nick, Tobin, Martin D, Varley, Ian, Wain, Louise V, Wray, Naomi R, Lindgren, Cecilia M, MacArthur, Daniel G, Waterworth, Dawn M, McCarthy, Mark I, Pedersen, Oluf, Khaw, Kay-Tee, Kiel, Douglas P, GEFOS Any-Type of Fracture Consortium, Pitsiladis, Yannis, Fuku, Noriyuki, Franks, Paul W, North, Kathryn N, van Duijn, Cornelia M, Mather, Karen A, Hansen, Torben, Hansson, Ola, Spector, Tim, Murabito, Joanne M, Richards, J Brent, Rivadeneira, Fernando, Langenberg, Claudia, Perry, John RB, Wareham, Nick J, and Scott, Robert A
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GEFOS Any-Type of Fracture Consortium ,Hand ,Humans ,Actins ,Transforming Growth Factor alpha ,Membrane Proteins ,Neoplasm Proteins ,Nuclear Proteins ,Repressor Proteins ,Hand Strength ,Cohort Studies ,Genetics ,Population ,Polymorphism ,Single Nucleotide ,Adult ,Aged ,Middle Aged ,European Continental Ancestry Group ,Female ,Male ,Genome-Wide Association Study ,Genetic Loci ,United Kingdom ,Prevention ,Genetics ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Musculoskeletal - Abstract
Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P
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- 2017
36. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples
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Kosmicki, Jack A, Samocha, Kaitlin E, Howrigan, Daniel P, Sanders, Stephan J, Slowikowski, Kamil, Lek, Monkol, Karczewski, Konrad J, Cutler, David J, Devlin, Bernie, Roeder, Kathryn, Buxbaum, Joseph D, Neale, Benjamin M, MacArthur, Daniel G, Wall, Dennis P, Robinson, Elise B, and Daly, Mark J
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Biological Sciences ,Genetics ,2.1 Biological and endogenous factors ,Autism Spectrum Disorder ,Exome ,Genetic Predisposition to Disease ,Genetic Variation ,Humans ,Intellectual Disability ,Neurodevelopmental Disorders ,Phenotype ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.
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- 2017
37. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity
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Saleheen, Danish, Natarajan, Pradeep, Armean, Irina M, Zhao, Wei, Rasheed, Asif, Khetarpal, Sumeet A, Won, Hong-Hee, Karczewski, Konrad J, O’Donnell-Luria, Anne H, Samocha, Kaitlin E, Weisburd, Benjamin, Gupta, Namrata, Zaidi, Mozzam, Samuel, Maria, Imran, Atif, Abbas, Shahid, Majeed, Faisal, Ishaq, Madiha, Akhtar, Saba, Trindade, Kevin, Mucksavage, Megan, Qamar, Nadeem, Zaman, Khan Shah, Yaqoob, Zia, Saghir, Tahir, Rizvi, Syed Nadeem Hasan, Memon, Anis, Hayyat Mallick, Nadeem, Ishaq, Mohammad, Rasheed, Syed Zahed, Memon, Fazal-ur-Rehman, Mahmood, Khalid, Ahmed, Naveeduddin, Do, Ron, Krauss, Ronald M, MacArthur, Daniel G, Gabriel, Stacey, Lander, Eric S, Daly, Mark J, Frossard, Philippe, Danesh, John, Rader, Daniel J, and Kathiresan, Sekar
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Genetics ,Clinical Research ,Human Genome ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,Apolipoprotein C-III ,Cohort Studies ,Consanguinity ,Coronary Disease ,Cytochrome P450 Family 2 ,DNA Mutational Analysis ,Dietary Fats ,Exome ,Fasting ,Female ,Gene Deletion ,Gene Frequency ,Genes ,Genetic Association Studies ,Homozygote ,Humans ,Interleukin-8 ,Male ,Middle Aged ,Myocardial Infarction ,Neuregulins ,Pakistan ,Pedigree ,Phenotype ,Phosphoproteins ,Postprandial Period ,RNA Splice Sites ,Reverse Genetics ,Sodium-Hydrogen Exchangers ,Triglycerides ,General Science & Technology - Abstract
A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (
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- 2017
38. Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease
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Gungor, Serdal, Oktay, Yavuz, Hiz, Semra, Aranguren-Ibáñez, Álvaro, Kalafatcilar, Ipek, Yaramis, Ahmet, Karaca, Ezgi, Yis, Uluc, Sonmezler, Ece, Ekinci, Burcu, Aslan, Mahmut, Yilmaz, Elmasnur, Özgör, Bilge, Balaraju, Sunitha, Szabo, Nora, Laurie, Steven, Beltran, Sergi, MacArthur, Daniel G., Hathazi, Denisa, Töpf, Ana, Roos, Andreas, Lochmuller, Hanns, Vernos, Isabelle, and Horvath, Rita
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- 2021
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39. Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development
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Jurgens, Julie A., Barry, Brenda J., Lemire, Gabrielle, Chan, Wai-Man, Whitman, Mary C., Shaaban, Sherin, Robson, Caroline D., MacKinnon, Sarah, England, Eleina M., McMillan, Hugh J., Kelly, Christopher, Pratt, Brandon M., O’Donnell-Luria, Anne, MacArthur, Daniel G., Boycott, Kym M., Hunter, David G., and Engle, Elizabeth C.
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- 2021
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40. A Quantitative Proteome Map of the Human Body
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Aguet, François, Anand, Shankara, Ardlie, Kristin G., Gabriel, Stacey, Getz, Gad, Graubert, Aaron, Hadley, Kane, Handsaker, Robert E., Huang, Katherine H., Kashin, Seva, MacArthur, Daniel G., Meier, Samuel R., Nedzel, Jared L., Nguyen, Duyen Y., Segrè, Ayellet V., Todres, Ellen, Balliu, Brunilda, Barbeira, Alvaro N., Battle, Alexis, Bonazzola, Rodrigo, Brown, Andrew, Brown, Christopher D., Castel, Stephane E., Conrad, Don, Cotter, Daniel J., Cox, Nancy, Das, Sayantan, de Goede, Olivia M., Dermitzakis, Emmanouil T., Engelhardt, Barbara E., Eskin, Eleazar, Eulalio, Tiffany Y., Ferraro, Nicole M., Flynn, Elise, Fresard, Laure, Gamazon, Eric R., Garrido-Martín, Diego, Gay, Nicole R., Guigó, Roderic, Hamel, Andrew R., He, Yuan, Hoffman, Paul J., Hormozdiari, Farhad, Hou, Lei, Im, Hae Kyung, Jo, Brian, Kasela, Silva, Kellis, Manolis, Kim-Hellmuth, Sarah, Kwong, Alan, Lappalainen, Tuuli, Li, Xin, Liang, Yanyu, Mangul, Serghei, Mohammadi, Pejman, Montgomery, Stephen B., Muñoz-Aguirre, Manuel, Nachun, Daniel C., Nobel, Andrew B., Oliva, Meritxell, Park, YoSon, Park, Yongjin, Parsana, Princy, Reverter, Ferran, Rouhana, John M., Sabatti, Chiara, Saha, Ashis, Skol, Andrew D., Stephens, Matthew, Stranger, Barbara E., Strober, Benjamin J., Teran, Nicole A., Viñuela, Ana, Wang, Gao, Wen, Xiaoquan, Wright, Fred, Wucher, Valentin, Zou, Yuxin, Ferreira, Pedro G., Li, Gen, Melé, Marta, Yeger-Lotem, Esti, Barcus, Mary E., Bradbury, Debra, Krubit, Tanya, McLean, Jeffrey A., Qi, Liqun, Robinson, Karna, Roche, Nancy V., Smith, Anna M., Sobin, Leslie, Tabor, David E., Undale, Anita, Bridge, Jason, Brigham, Lori E., Foster, Barbara A., Gillard, Bryan M., Hasz, Richard, Hunter, Marcus, Johns, Christopher, Johnson, Mark, Karasik, Ellen, Kopen, Gene, Leinweber, William F., McDonald, Alisa, Moser, Michael T., Myer, Kevin, Ramsey, Kimberley D., Roe, Brian, Shad, Saboor, Thomas, Jeffrey A., Walters, Gary, Washington, Michael, Wheeler, Joseph, Jewell, Scott D., Rohrer, Daniel C., Valley, Dana R., Davis, David A., Mash, Deborah C., Branton, Philip A., Barker, Laura K., Gardiner, Heather M., Mosavel, Maghboeba, Siminoff, Laura A., Flicek, Paul, Haeussler, Maximilian, Juettemann, Thomas, Kent, W. James, Lee, Christopher M., Powell, Conner C., Rosenbloom, Kate R., Ruffier, Magali, Sheppard, Dan, Taylor, Kieron, Trevanion, Stephen J., Zerbino, Daniel R., Abell, Nathan S., Akey, Joshua, Chen, Lin, Demanelis, Kathryn, Doherty, Jennifer A., Feinberg, Andrew P., Hansen, Kasper D., Hickey, Peter F., Jasmine, Farzana, Kaul, Rajinder, Kibriya, Muhammad G., Li, Jin Billy, Li, Qin, Linder, Sandra E., Pierce, Brandon L., Rizzardi, Lindsay F., Smith, Kevin S., Stamatoyannopoulos, John, Tang, Hua, Carithers, Latarsha J., Guan, Ping, Koester, Susan E., Little, A. Roger, Moore, Helen M., Nierras, Concepcion R., Rao, Abhi K., Vaught, Jimmie B., Volpi, Simona, Jiang, Lihua, Wang, Meng, Lin, Shin, Jian, Ruiqi, Li, Xiao, Chan, Joanne, Dong, Guanlan, Fang, Huaying, Robinson, Aaron E., and Snyder, Michael P.
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- 2020
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41. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations
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Connaughton, Dervla M., Dai, Rufeng, Owen, Danielle J., Marquez, Jonathan, Mann, Nina, Graham-Paquin, Adda L., Nakayama, Makiko, Coyaud, Etienne, Laurent, Estelle M.N., St-Germain, Jonathan R., Blok, Lot Snijders, Vino, Arianna, Klämbt, Verena, Deutsch, Konstantin, Wu, Chen-Han Wilfred, Kolvenbach, Caroline M., Kause, Franziska, Ottlewski, Isabel, Schneider, Ronen, Kitzler, Thomas M., Majmundar, Amar J., Buerger, Florian, Onuchic-Whitford, Ana C., Youying, Mao, Kolb, Amy, Salmanullah, Daanya, Chen, Evan, van der Ven, Amelie T., Rao, Jia, Ityel, Hadas, Seltzsam, Steve, Rieke, Johanna M., Chen, Jing, Vivante, Asaf, Hwang, Daw-Yang, Kohl, Stefan, Dworschak, Gabriel C., Hermle, Tobias, Alders, Mariëlle, Bartolomaeus, Tobias, Bauer, Stuart B., Baum, Michelle A., Brilstra, Eva H., Challman, Thomas D., Zyskind, Jacob, Costin, Carrie E., Dipple, Katrina M., Duijkers, Floor A., Ferguson, Marcia, Fitzpatrick, David R., Fick, Roger, Glass, Ian A., Hulick, Peter J., Kline, Antonie D., Krey, Ilona, Kumar, Selvin, Lu, Weining, Marco, Elysa J., Wentzensen, Ingrid M., Mefford, Heather C., Platzer, Konrad, Povolotskaya, Inna S., Savatt, Juliann M., Shcherbakova, Natalia V., Senguttuvan, Prabha, Squire, Audrey E., Stein, Deborah R., Thiffault, Isabelle, Voinova, Victoria Y., Somers, Michael J.G., Ferguson, Michael A., Traum, Avram Z., Daouk, Ghaleb H., Daga, Ankana, Rodig, Nancy M., Terhal, Paulien A., van Binsbergen, Ellen, Eid, Loai A., Tasic, Velibor, Rasouly, Hila Milo, Lim, Tze Y., Ahram, Dina F., Gharavi, Ali G., Reutter, Heiko M., Rehm, Heidi L., MacArthur, Daniel G., Lek, Monkol, Laricchia, Kristen M., Lifton, Richard P., Xu, Hong, Mane, Shrikant M., Sanna-Cherchi, Simone, Sharrocks, Andrew D., Raught, Brian, Fisher, Simon E., Bouchard, Maxime, Khokha, Mustafa K., Shril, Shirlee, and Hildebrandt, Friedhelm
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- 2020
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42. Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness
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Töpf, Ana, Johnson, Katherine, Bates, Adam, Phillips, Lauren, Chao, Katherine R., England, Eleina M., Laricchia, Kristen M., Mullen, Thomas, Valkanas, Elise, Xu, Liwen, Bertoli, Marta, Blain, Alison, Casasús, Ana B., Duff, Jennifer, Mroczek, Magdalena, Specht, Sabine, Lek, Monkol, Ensini, Monica, MacArthur, Daniel G., Akay, Ela, Alonso-Pérez, Jorge, Baets, Jonathan, Barisic, Nina, Bastian, Alexandra, Borell, Sabine, Chamova, Teodora, Claeys, Kristl, Colomer, Jaume, Coppens, Sandra, Deconinck, Nicolas, de Ridder, Willem, Díaz-Manera, Jordi, Domínguez-González, Cristina, Duncan, Alexis, Durmus, Hacer, Fahmy, Nagia A., Farrugia, Maria Elena, Fernández-Torrón, Roberto, Gonzalez-Quereda, Lidia, Haberlova, Jana, von der Hagen, Maja, Hahn, Andreas, Jakovčević, Antonia, Jerico Pascual, Ivonne, Kapetanovic, Solange, Kenina, Viktorija, Kirschner, Janbernd, Klein, Andrea, Kölbel, Heike, Kostera-Pruszczyk, Anna, Kulshrestha, Richa, Lähdetie, Jaana, Layegh, Mahsa, Longman, Cheryl, López de Munain, Adolfo, Loscher, Wolfgang, Lusakowska, Anna, Maddison, Paul, Magot, Armelle, Majumdar, Anirban, Martí, Pilar, Martínez Arroyo, Amaia, Mazanec, Radim, Mercier, Sandra, Mongini, Tiziana, Muelas, Nuria, Nascimento, Andrés, Nafissi, Shahriar, Omidi, Shirin, Ortez, Carlos, Paquay, Stéphanie, Pereon, Yann, Perić, Stojan, Ponzalino, Valentina, Rakočević Stojanović, Vidosava, Remiche, Gauthier, Rodríguez Sainz, Aida, Rudnik, Sabine, Sanchez Albisua, Iciar, Santos, Manuela, Schara, Ulrike, Shatillo, Andriy, Sertić, Jadranka, Stephani, Ulrich, Strang-Karlsson, Sonja, Sznajer, Yves, Tanev, Ani, Tournev, Ivailo, Van den Bergh, Peter, Van Parijs, Vinciane, Vílchez, Juan, Vill, Katharina, Vissing, John, Wallgren-Pettersson, Carina, Wanschitz, Julia, Willis, Tracey, Witting, Nanna, Zulaica, Miren, and Straub, Volker
- Published
- 2020
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43. Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer
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Aguet, Francois, Ding, Li, Demchok, John A., Mensah, Michael K.A., Caesar-Johnson, Samantha, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Alfoldi, Jessica, Karczewski, Konrad J., MacArthur, Daniel G., Meyerson, Matthew, Benz, Christopher, Stuart, Joshua M., Carrot-Zhang, Jian, Chambwe, Nyasha, Damrauer, Jeffrey S., Knijnenburg, Theo A., Robertson, A. Gordon, Yau, Christina, Zhou, Wanding, Berger, Ashton C., Huang, Kuan-lin, Newberg, Justin Y., Mashl, R. Jay, Romanel, Alessandro, Sayaman, Rosalyn W., Demichelis, Francesca, Felau, Ina, Frampton, Garrett M., Han, Seunghun, Hoadley, Katherine A., Kemal, Anab, Laird, Peter W., Lazar, Alexander J., Le, Xiuning, Oak, Ninad, Shen, Hui, Wong, Christopher K., Zenklusen, Jean C., Ziv, Elad, Cherniack, Andrew D., and Beroukhim, Rameen
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- 2020
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44. Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone
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Marchant, Rhett G., primary, Bryen, Samantha J., additional, Bahlo, Melanie, additional, Cairns, Anita, additional, Chao, Katherine R., additional, Corbett, Alastair, additional, Davis, Mark R., additional, Ganesh, Vijay S., additional, Ghaoui, Roula, additional, Jones, Kristi J., additional, Kornberg, Andrew J., additional, Lek, Monkol, additional, Liang, Christina, additional, MacArthur, Daniel G., additional, Oates, Emily C., additional, O'Donnell‐Luria, Anne, additional, O'Grady, Gina L., additional, Osei‐Owusu, Ikeoluwa A., additional, Rafehi, Haloom, additional, Reddel, Stephen W., additional, Roxburgh, Richard H., additional, Ryan, Monique M., additional, Sandaradura, Sarah A., additional, Scott, Liam W., additional, Valkanas, Elise, additional, Weisburd, Ben, additional, Young, Helen, additional, Evesson, Frances J., additional, Waddell, Leigh B., additional, and Cooper, Sandra T., additional
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- 2024
- Full Text
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45. High-throughput discovery of novel developmental phenotypes.
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Dickinson, Mary E, Flenniken, Ann M, Ji, Xiao, Teboul, Lydia, Wong, Michael D, White, Jacqueline K, Meehan, Terrence F, Weninger, Wolfgang J, Westerberg, Henrik, Adissu, Hibret, Baker, Candice N, Bower, Lynette, Brown, James M, Caddle, L Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J, Denegre, James M, Doe, Brendan, Dolan, Mary E, Edie, Sarah M, Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R, Hsu, Chih-Wei, Johnson, Sara J, Kalaga, Sowmya, Keith, Lance C, Lanoue, Louise, Lawson, Thomas N, Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L, Newbigging, Susan, Nutter, Lauryl MJ, Peterson, Kevin A, Ramirez-Solis, Ramiro, Rowland, Douglas J, Ryder, Edward, Samocha, Kaitlin E, Seavitt, John R, Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G, Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B, Wong, Leeyean, Yoshiki, Atsushi, International Mouse Phenotyping Consortium, Jackson Laboratory, Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS), Charles River Laboratories, MRC Harwell, Toronto Centre for Phenogenomics, Wellcome Trust Sanger Institute, RIKEN BioResource Center, MacArthur, Daniel G, Tocchini-Valentini, Glauco P, Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C, Justice, Monica J, Parkinson, Helen E, Moore, Mark, Wells, Sara, Braun, Robert E, Svenson, Karen L, de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R Mark, Brown, Steve DM, Adams, David J, Lloyd, KC Kent, McKerlie, Colin, Beaudet, Arthur L, Bućan, Maja, and Murray, Stephen A
- Subjects
International Mouse Phenotyping Consortium ,Jackson Laboratory ,Infrastructure Nationale PHENOMIN ,Institut Clinique de la Souris ,Charles River Laboratories ,MRC Harwell ,Toronto Centre for Phenogenomics ,Wellcome Trust Sanger Institute ,RIKEN BioResource Center ,Animals ,Mice ,Inbred C57BL ,Mice ,Knockout ,Humans ,Mice ,Disease ,Imaging ,Three-Dimensional ,Conserved Sequence ,Sequence Homology ,Phenotype ,Penetrance ,Mutation ,Polymorphism ,Single Nucleotide ,Genes ,Essential ,Genes ,Lethal ,Embryo ,Mammalian ,Genome-Wide Association Study ,High-Throughput Screening Assays ,Biotechnology ,Human Genome ,Pediatric ,Congenital Structural Anomalies ,Genetics ,2.1 Biological and endogenous factors ,General Science & Technology - Abstract
Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
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- 2016
46. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome
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Kim, Jung-Hyun, Shinde, Deepali N, Reijnders, Margot RF, Hauser, Natalie S, Belmonte, Rebecca L, Wilson, Gregory R, Bosch, Daniëlle GM, Bubulya, Paula A, Shashi, Vandana, Petrovski, Slavé, Stone, Joshua K, Park, Eun Young, Veltman, Joris A, Sinnema, Margje, Stumpel, Connie TRM, Draaisma, Jos M, Nicolai, Joost, Genomics, University of Washington Center for Mendelian, Yntema, Helger G, Lindstrom, Kristin, de Vries, Bert BA, Jewett, Tamison, Santoro, Stephanie L, Vogt, Julie, Study, Deciphering Developmental Disorders, Bachman, Kristine K, Seeley, Andrea H, Krokosky, Alyson, Turner, Clesson, Rohena, Luis, Hempel, Maja, Kortüm, Fanny, Lessel, Davor, Neu, Axel, Strom, Tim M, Wieczorek, Dagmar, Bramswig, Nuria, Laccone, Franco A, Behunova, Jana, Rehder, Helga, Gordon, Christopher T, Rio, Marlène, Romana, Serge, Tang, Sha, El-Khechen, Dima, Cho, Megan T, McWalter, Kirsty, Douglas, Ganka, Baskin, Berivan, Begtrup, Amber, Funari, Tara, Schoch, Kelly, Stegmann, Alexander PA, Stevens, Servi JC, Zhang, Dong-Er, Traver, David, Yao, Xu, MacArthur, Daniel G, Brunner, Han G, Mancini, Grazia M, Myers, Richard M, Owen, Laurie B, Lim, Ssang-Taek, Stachura, David L, Vissers, Lisenka ELM, and Ahn, Eun-Young Erin
- Subjects
Brain Disorders ,Congenital Structural Anomalies ,Neurosciences ,Mental Health ,Clinical Research ,Genetics ,Pediatric ,Intellectual and Developmental Disabilities (IDD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Congenital ,Animals ,Brain ,DNA-Binding Proteins ,Developmental Disabilities ,Eye Abnormalities ,Female ,Genes ,Essential ,Haploinsufficiency ,Head ,Heterozygote ,Humans ,Intellectual Disability ,Male ,Metabolic Diseases ,Minor Histocompatibility Antigens ,Mutation ,Pedigree ,RNA Splicing ,RNA ,Messenger ,Spine ,Syndrome ,Zebrafish ,University of Washington Center for Mendelian Genomics ,Deciphering Developmental Disorders Study ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
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- 2016
47. Analysis of protein-coding genetic variation in 60,706 humans.
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Lek, Monkol, Karczewski, Konrad J, Minikel, Eric V, Samocha, Kaitlin E, Banks, Eric, Fennell, Timothy, O'Donnell-Luria, Anne H, Ware, James S, Hill, Andrew J, Cummings, Beryl B, Tukiainen, Taru, Birnbaum, Daniel P, Kosmicki, Jack A, Duncan, Laramie E, Estrada, Karol, Zhao, Fengmei, Zou, James, Pierce-Hoffman, Emma, Berghout, Joanne, Cooper, David N, Deflaux, Nicole, DePristo, Mark, Do, Ron, Flannick, Jason, Fromer, Menachem, Gauthier, Laura, Goldstein, Jackie, Gupta, Namrata, Howrigan, Daniel, Kiezun, Adam, Kurki, Mitja I, Moonshine, Ami Levy, Natarajan, Pradeep, Orozco, Lorena, Peloso, Gina M, Poplin, Ryan, Rivas, Manuel A, Ruano-Rubio, Valentin, Rose, Samuel A, Ruderfer, Douglas M, Shakir, Khalid, Stenson, Peter D, Stevens, Christine, Thomas, Brett P, Tiao, Grace, Tusie-Luna, Maria T, Weisburd, Ben, Won, Hong-Hee, Yu, Dongmei, Altshuler, David M, Ardissino, Diego, Boehnke, Michael, Danesh, John, Donnelly, Stacey, Elosua, Roberto, Florez, Jose C, Gabriel, Stacey B, Getz, Gad, Glatt, Stephen J, Hultman, Christina M, Kathiresan, Sekar, Laakso, Markku, McCarroll, Steven, McCarthy, Mark I, McGovern, Dermot, McPherson, Ruth, Neale, Benjamin M, Palotie, Aarno, Purcell, Shaun M, Saleheen, Danish, Scharf, Jeremiah M, Sklar, Pamela, Sullivan, Patrick F, Tuomilehto, Jaakko, Tsuang, Ming T, Watkins, Hugh C, Wilson, James G, Daly, Mark J, MacArthur, Daniel G, and Exome Aggregation Consortium
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Exome Aggregation Consortium ,Humans ,Rare Diseases ,Proteome ,Sample Size ,DNA Mutational Analysis ,Phenotype ,Genetic Variation ,Exome ,Datasets as Topic ,Clinical Research ,Biotechnology ,Human Genome ,Genetics ,Genetic Testing ,2.1 Biological and endogenous factors ,Aetiology ,Generic health relevance ,General Science & Technology - Abstract
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
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- 2016
48. Genetic regulatory variation in populations informs transcriptome analysis in rare disease
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Mohammadi, Pejman, Castel, Stephane E., Cummings, Beryl B., Einson, Jonah, Sousa, Christina, Hoffman, Paul, Donkervoort, Sandra, Jiang, Zhuoxun, Mohassel, Payam, Foley, A. Reghan, Wheeler, Heather E., Im, Hae Kyung, Bonnemann, Carsten G., MacArthur, Daniel G., and Lappalainen, Tuuli
- Published
- 2019
49. Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy
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Bryen, Samantha J., Oates, Emily C., Evesson, Frances J., Lu, Jessica K., Waddell, Leigh B., Joshi, Himanshu, Ryan, Monique M., Cummings, Beryl B., McLean, Catriona A., MacArthur, Daniel G., Kornberg, Andrew J., and Cooper, Sandra T.
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- 2021
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50. The effect of LRRK2 loss-of-function variants in humans
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Whiffin, Nicola, Armean, Irina M., Kleinman, Aaron, Marshall, Jamie L., Minikel, Eric V., Goodrich, Julia K., Quaife, Nicholas M., Cole, Joanne B., Wang, Qingbo, Karczewski, Konrad J., Cummings, Beryl B., Francioli, Laurent, Laricchia, Kristen, Guan, Anna, Alipanahi, Babak, Morrison, Peter, Baptista, Marco A. S., Merchant, Kalpana M., Ware, James S., Havulinna, Aki S., Iliadou, Bozenna, Lee, Jung-Jin, Nadkarni, Girish N., Whiteman, Cole, Daly, Mark, Esko, Tõnu, Hultman, Christina, Loos, Ruth J. F., Milani, Lili, Palotie, Aarno, Pato, Carlos, Pato, Michele, Saleheen, Danish, Sullivan, Patrick F., Alföldi, Jessica, Cannon, Paul, and MacArthur, Daniel G.
- Published
- 2020
- Full Text
- View/download PDF
Catalog
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