Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

作者：Daniel Taliun, Daniel Harris, Michael D. Kessler, Jedidiah Carlson, Zachary A. Szpiech, Raúl Torres, Sarah A. Gagliano Taliun, André Corvelo, Stephanie M. Gogarten, Hyun Min Kang, Achilleas Pitsillides, Jonathon LeFaive, Seung‐been Lee, Xiaowen Tian, Brian L. Browning, Sayantan Das, Anne‐Katrin Emde, Wayne E. Clarke, Douglas P. Loesch, Amol C. Shetty, Thomas W. Blackwell, Albert V. Smith, Quenna Wong, Xiaoming Liu, Matthew P. Conomos, Dean Bobo, François Aguet, Christine M. Albert, Álvaro Alonso, Kristin Ardlie, Dan E. Arking, Stella Aslibekyan, Paul L. Auer, John Barnard, R. Graham Barr, Lucas Barwick, Lewis C. Becker, Rebecca Beer, Emelia J. Benjamin, Lawrence F. Bielak, John Blangero, Michael Boehnke, Donald W. Bowden, Jennifer A. Brody, Esteban G. Burchard, Brian E. Cade, James F. Casella, Brandon Chalazan, Daniel I. Chasman, Yii‐Der Ida Chen, Michael H. Cho, Seung Hoan Choi, Mina K. Chung, Clary B. Clish, Adolfo Correa, Joanne E. Curran, Brian Custer, Dawood Darbar, Michelle Daya, Mariza de Andrade, Dawn L. DeMeo, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Celeste Eng, Diane Fatkin, Tasha E. Fingerlin, Lukas Forer, Myriam Fornage, Nora Franceschini, Christian Fuchsberger, Stephanie M. Fullerton, Søren Germer, Mark T. Gladwin, Daniel J. Gottlieb, Xiuqing Guo, Michael E. Hall, Jiang He, Nancy L. Heard‐Costa, Susan R. Heckbert, Marguerite R. Irvin, Jill M. Johnsen, Andrew D. Johnson, Robert C. Kaplan, Sharon L. R. Kardia, Tanika N. Kelly, Shannon Kelly, Eimear E. Kenny, Douglas P. Kiel, Robert Klemmer, Barbara A. Konkle, Charles Kooperberg, Anna Köttgen, Leslie A. Lange, Jessica Lasky‐Su, Daniel Levy, Xihong Lin, Keng‐Han Lin, Chunyu Liu, Ruth J. F. Loos, Lori Garman, Robert E. Gerszten, Steven A. Lubitz, Kathryn L. Lunetta, Angel C. Y. Mak, Ani Manichaikul, Alisa K. Manning, Rasika A. Mathias, David D. McManus, Stephen T. McGarvey, James B. Meigs, Deborah A. Meyers, Julie Mikulla, Mollie Minear, Braxton D. Mitchell, Sanghamitra Mohanty, May E. Montasser, Courtney G. Montgomery, Alanna C. Morrison, Joanne M. Murabito, Andrea Natale, Pradeep Natarajan, Sarah C. Nelson, Kari E. North, Jeffrey R. O’Connell, Nicholette D. Palmer, Nathan Pankratz, Gina M. Peloso, Patricia A. Peyser, Jacob Pleiness, Wendy S. Post, Bruce M. Psaty, D. C. Rao, Susan Redline, Alex P. Reiner, Dan M. Roden, Jerome I. Rotter, Ingo Ruczinski, Chloé Sarnowski, Sebastian Schoenherr, David A. Schwartz, Jeong‐Sun Seo, Sudha Seshadri, Vivien Sheehan, Wayne H.-H. Sheu, M. Benjamin Shoemaker, Nicholas L. Smith, Jennifer A. Smith, Nona Sotoodehnia, Adrienne M. Stilp, Weihong Tang, Kent D. Taylor, Marilyn J. Telen, Timothy A. Thornton, Russell P. Tracy, David Van Den Berg, Ramachandran S. Vasan, Karine A. Viaud‐Martinez, Scott Vrieze, Daniel E. Weeks, Bruce S. Weir, Scott T. Weiss, Lu‐Chen Weng, Cristen J. Willer, Yingze Zhang, Xutong Zhao, Donna K. Arnett, Allison E. Ashley‐Koch, Kathleen C. Barnes, Eric Boerwinkle, Stacey Gabriel, Richard A. Gibbs, Kenneth Rice, Stephen S. Rich, Edwin K. Silverman, Pankaj Qasba, Weiniu Gan, Namiko Abe, Laura Almasy, Seth A. Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum‐Bowden, Tim Assimes, Dimitrios Avramopoulos, Emily Barron‐Casella, Terri Beaty, Gerald J. Beck, Diane M. Becker, Amber L. Beitelshees, Takis Benos, Marcos Bezerra, Joshua C. Bis, Russell Bowler, Ulrich Broeckel, Jai Broome, Karen Bunting, Carlos D. Bustamante, Erin Buth, Jonathan Cardwell, Vincent J. Carey, Cara L. Carty, Richard Casaburi, Peter J. Castaldi, Mark Chaffin, Christy Chang, Yi‐Cheng Chang, Sameer Chavan, Bo‐Juen Chen, Wei‐Min Chen, Lee‐Ming Chuang, Ren‐Hua Chung, Suzy Comhair, Elaine Cornell, Carolyn Crandall, James D. Crapo, Jeffrey L. Curtis, Coleen Damcott, Sean P. David, Colleen Davis, Lisa de las Fuentes, Michael R. DeBaun, Ranjan Deka, Scott E. Devine, Qing Duan, Ravi Duggirala, Jon Peter Durda, Charles B. Eaton, Lynette Ekunwe, Adel Boueiz, Serpil C. Erzurum, Charles R. Farber, Matthew Flickinger, Myriam Fornage, Chris Frazar, Mao Fu, Lucinda Fulton, Shanshan Gao, Yan Gao, Margery Gass, Bruce D. Gelb, Xiaoqi Geng, Mark W. Geraci, Auyon Ghosh, Chris Gignoux, David C. Glahn, Da‐Wei Gong, Harald H.H. Göring, Sharon Graw, Daniel Grine, C. Charles Gu, Yue Guan, Namrata Gupta, Jeff Haessler, Nicola L. Hawley, Ben Heavner, David Herrington, Craig P. Hersh, Bertha Hidalgo, James E. Hixson, Brian D. Hobbs, John E. Hokanson, Elliott Hong, Karin F. Hoth, Chao A. Hsiung, Yi‐Jen Hung, Haley Huston, Chii Min Hwu, Rebecca Jackson, Deepti Jain, Min A. Jhun, Craig Johnson, Rich Johnston, Kimberly Marie Jones, Sekar Kathiresan, Alyna Khan, Wonji Kim, Gregory L. Kinney, Holly Kramer, Christoph Lange, Ethan M. Lange, Leslie Lange, Cecelia Laurie, Cecelia Laurie, Meryl LeBoff, Seunggeun Shawn Lee, Wen‐Jane Lee, Wen-Jane Lee, D. Levine, Joshua Lewis, Yun Li, Henry J. Lin, Honghuang Lin, Keng Han Lin, Simin Liu, Ching‐Ti Liu, Yu Liu, Yu Liu, James Luo, Michael Mahaney, Barry Make, JoAnn Manson, Lauren Margolin, Lisa Martin, Mathai Susan, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Daniel McGoldrick, Caitlin McHugh, Hao Mei, Luisa Mestroni, Ryan L. Minster, Ryan L. Minster, Matt Moll, Arden Moscati, Solomon Musani, Stanford Mwasongwe, Josyf C. Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Bonnie Neltner, H. Ochs-Balcom, David Paik, J Pankow, Afshin Parsa, Juan Manuel Peralta, Marco Perez, James Perry, Ulrike Peters, Lawrence S. Phillips, Toni Pollin, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Dandi Qiao, Zhaohui Qin, Nicholas Rafaels, Laura J. Rasmussen‐Torvik, Laura Rasmussen-Torvik, Aakrosh Ratan, Robert Reed, Elizabeth Regan, Muagututi‘a Sefuiva Reupena, Carolina Roselli, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Ester Cerdeira Sabino, Danish Saleheen, Shabnam Salimi, Salzberg Sa, Kevin Sandow, Vijay G. Sankaran, Christopher Scheller, Ellen Schmidt, Karen Schwander, Frank Sciurba, Jonathan G. Seidman, J G Seidman, Stephanie L. Sherman, Aniket Shetty, Wayne Hui-Heng Sheu, Brian Silver, Tanja Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, M Snyder, Tamar Sofer, G. Storm, Elizabeth Streeten, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Hua Tang, Margaret Taub, Simeon I. Taylor, Simeon Taylor, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Michael Tsai, Dhananjay Vaidya, Peter VandeHaar, Tarik Walker, Robert Wallace, Avram Walts, Heming Wang, Heming Wang, Karol Watson, Jennifer Wessel, L. Keoki Williams, L. Keoki Williams, Carla Wilson, Huichun Xu, Huichun Xu, Lisa Yanek, Rongze Yang, Rongze Yang, Norann Zaghloul, Maryam Zekavat, Wei Zhao, Wei Zhao, Degui Zhi, Xiaofeng Zhu, Xiaofeng Zhu, George J. Papanicolaou, Deborah A. Nickerson, Sharon R. Browning, Michael C. Zody, Sebastian Zöllner, James G. Wilson, L. Adrienne Cupples, Cathy C. Laurie, Cathy C. Laurie, Cashell E. Jaquish, Ryan D. Hernandez, Timothy D. O’Connor, Gonçalo R. Abecasis · 发表于：Nature · 年份：2021 · DOI：10.1038/s41586-021-03205-y · 被引用次数：2362 · 研究领域：Genetic Associations and Epidemiology、Genomics and Rare Diseases、RNA Research and Splicing

Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermor...