A deep catalogue of protein-coding variation in 983,578 individuals

作者：Kathie Sun, Xiaodong Bai, Siying Chen, Suying Bao, Chuanyi Zhang, Manav Kapoor, Joshua Backman, Tyler Joseph, Evan K. Maxwell, George Mitra, Alexander Gorovits, Adam J. Mansfield, Boris Boutkov, Sujit Gokhale, Lukas Habegger, Anthony Marcketta, Adam E. Locke, Liron Ganel, Alicia Hawes, Michael D. Kessler, Deepika Sharma, Jeffrey Staples, Jonas Bovijn, Sahar Gelfman, Alessandro Di Gioia, Veera M. Rajagopal, Alexander Lopez, Jennifer Rico Varela, Jesús Alegre-Díaz, Jaime Berúmen, Roberto Tapia‐Conyer, Pablo Kuri‐Morales, Jason Torres, Jonathan Emberson, Rory Collins, RGC Management and Leadership Team, Gonçalo Abecasis, Giovanni Coppola, Andrew Deubler, Aris Economides, Adolfo A. Ferrando, Luca A. Lotta, Alan R. Shuldiner, Katherine Siminovitch, Sequencing and Lab Operations, Christina Beechert, Erin D. Brian, Laura M. Cremona, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Justin Mower, Mudasar Sarwar, Jeffrey C. Staples, Sean Yu, Aaron Zhang, Genome Informatics and Data Engineering, Andrew Bunyea, Krishna Pawan Punuru, Sanjay Sreeram, Gisu Eom, Benjamin Sultan, Rouel Lanche, Vrushali Mahajan, Eliot Austin, Sean O’Keeffe, Razvan Panea, Tommy Polanco, Ayesha Rasool, Lance Zhang, Evan Edelstein, Ju Guan, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Evan K. Maxwell, Kathie Sun, Analytical Genetics and Data Science, Manuel Allen Revez Ferreira, Kathy Burch, Adrián I. Campos, Lei Chen, Sam Choi, Amy Damask, Sheila M. Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher E. Gillies, Lauren Gurski, Joseph Herman, Eric Jorgenson, Michael D. Kessler, Jack A. Kosmicki, Nan Lin, Adam E. Locke, Priyanka Nakka, Karl Landheer, Olivier Delaneau, Maya Ghoussaini, Joelle Mbatchou, Arden Moscati, Aditeya Pandey, Anita Pandit, Charles Paulding, Jonathan Ross, Carlo Sidore, Eli Stahl, Maria Suciu, Peter VandeHaar, Sailaja Vedantam, Scott Vrieze, Jingning Zhang, Rujin Wang, Kuan-Han H. Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Kyoko Watanabe, Mira Tang, Therapeutic Area Genetics, Brian D. Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit D. Joshi, Antoine Baldassari, Cristen J. Willer, Sarah E. Graham, Ernst Mayerhofer, Mary E. Haas, Niek Verweij, George Hindy, Tanima De, Parsa Akbari, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Juan L. Rodríguez-Flores, Moeen Riaz, Gannie Tzoneva, Momodou W. Jallow, Anna Alkelai, Ariane Ayer, Veera M. Rajagopal, Vijay Kumar, Jacqueline M. Otto, Neelroop Parikshak, Ayşegül Güvenek, José Brás, Silvia Álvarez, Jessie Brown, Jing He, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina A. Zavala, Lyndon J. Mitnaul, Marcus B. Jones, Esteban Chen, Michelle G. LeBlanc, Jason Mighty, Nirupama Nishtala, Nadia A. Rana, Jennifer Rico‐Varela, Jaimee Hernandez, Senior Partnerships and Business Operations, Alison Fenney, Randi Schwartz, Jody Hankins, Samuel F. M. Hart, Business Operations and Administrative Coordinators, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, RGC-ME Cohort Partners, Accelerated Cures, David I. Gwynne, African Descent and Glaucoma Evaluation Study (ADAGES) III, Jerome I. Rotter, Robert Weinreb, Age-related macular degeneration in the Amish, Jonathan L. Haines, Margaret A. Pericak‐Vance, Dwight Stambolian, Nir Barzilai, Yousin Suh, Zhengdong Zhang, Amish Connectome Project, Elliot Hong, Braxton D. Mitchell, Nicholas B. Blackburn, Simon Broadley, Marzena J. Fabis‐Pedrini, Vilija Jokubaitis, Allan G. Kermode, Trevor J. Kilpatrick, Jeanette Lechner-Scott, Stephen J Leslie, Bennet J. McComish, Allan Motyer, Grant P. Parnell, Rodney J. Scott, Bruce Taylor, Justin P. Rubio, Danish Saleheen, Ken Kaufman, Leah C. Kottyan, Lisa W. Martin, Marc E. Rothenberg, Abdullah Mahmood Ali, Azra Raza, Dallas Heart Study, Jonathan Cohen, Adam R. Glassman, William E. Kraus, Christopher B. Newgard, Svati H. Shah, Jamie E. Craig, Alex W. Hewitt, Indiana Biobank, Naga Chalasani, Tatiana Foroud, Suthat Liangpunsakul, Nancy J. Cox, M. Eileen Dolan, Omar El-Charif, Lois B. Travis, Heather E. Wheeler, Eric R. Gamazon, Kaiser Permanente, Lori C. Sakoda, John S. Witte, Kostantinos Lazaridis, Mexico City Prospective Study (MCPS), MyCode-DiscovEHR Geisinger Health System Biobank, Adam H. Buchanan, David J. Carey, Christa Lese Martin, Michelle N. Meyer, Kyle Retterer, David D.K. Rolston, Nirmala Akula, Emily Besançon, Sevilla D. Detera‐Wadleigh, Layla Kassem, Francis J. McMahon, Thomas G. Schulze, Allan Gordon, Maureen E. Smith, John Varga, Penn Medicine Biobank, Yuki Bradford, Scott M. Damrauer, Stephanie DerOhannessian, Theodore G. Drivas, Scott Dudek, Joseph Dunn, Ned Haubein, Renae Judy, Yi-An Ko, Colleen Morse Kripke, Meghan Livingstone, Nawar Naseer, Kyle P. Nerz, Afiya Poindexter, Marjorie Risman, Salma Santos, Giorgio Sirugo, Julia Stephanowski, Teo Tran, Fred Vadivieso, Anurag Verma, Shefali S. Verma, JoEllen Weaver, Colin Wollack, Daniel J. Rader, Marylyn D. Ritchie, Primary Open-Angle African American Glaucoma Genetics (POAAG) study, Joan M. O’Brien, Regeneron–Mt. Sinai BioMe Biobank, Erwin P. Böttinger, Judy H. Cho, UAB GWAS in African Americans with rheumatoid arthritis, S. Louis Bridges, UAB Whole exome sequencing of systemic lupus erythematosus patients, Robert P. Kimberly, Marlena S. Fejzo, Richard A. Spritz, James T. Elder, Rajan P. Nair, Philip E. Stuart, Lam C. Tsoi, Robert Dent, Ruth McPherson, Brendan J. Keating, Erin E. Kershaw, Georgios I. Papachristou, David C. Whitcomb, Shervin Assassi, Maureen D. Mayes, Eric D. Austin, Michael Cantor, Timothy A. Thornton, Hyun Min Kang, John D. Overton, Alan R. Shuldiner, María Laura Cremona, Mona Nafde, Aris Baras, Gonçalo Abecasis, Jonathan Marchini, Jeffrey G. Reid, William Salerno, Suganthi Balasubramanian · 发表于：Nature · 年份：2024 · DOI：10.1038/s41586-024-07556-0 · 被引用次数：113 · 研究领域：Genetics, Bioinformatics, and Biomedical Research、Machine Learning in Bioinformatics、Gene expression and cancer classification

. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.