Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program
Authors: Taliun Daniel , Harris Daniel N. , Kessler Michael D. , Carlson Jedidiah , Szpiech Zachary A. , Torres Raul , Taliun Sarah A. Gagliano , Corvelo André , Gogarten Stephanie M. , Kang Hyun Min , Pitsillides Achilleas N. , LeFaive Jonathon , Lee Seung-been , Tian Xiaowen , Browning Brian L. , Das Sayantan , Emde Anne-Katrin , Clarke Wayne E. , Loesch Douglas P. , Shetty Amol C. , Blackwell Thomas W. , Smith Albert V. , Wong Quenna , Liu Xiaoming , Conomos Matthew P. , Bobo Dean M. , Aguet François , Albert Christine , Alonso Alvaro , Ardlie Kristin G. , Arking Dan E. , Aslibekyan Stella , Auer Paul L. , Barnard John , Barr R. Graham , Barwick Lucas , Becker Lewis C. , Beer Rebecca L. , Benjamin Emelia J. , Bielak Lawrence F. , Blangero John , Boehnke Michael , Bowden Donald W. , Brody Jennifer A. , Burchard Esteban G. , Cade Brian E. , Casella James F. , Chalazan Brandon , Chasman Daniel I. , Chen Yii-Der Ida , Cho Michael H. , Choi Seung Hoan , Chung Mina K. , Clish Clary B. , Correa Adolfo , Curran Joanne E. , Custer Brian , Darbar Dawood , Daya Michelle , de Andrade Mariza , DeMeo Dawn L. , Dutcher Susan K. , Ellinor Patrick T. , Emery Leslie S. , Eng Celeste , Fatkin Diane , Fingerlin Tasha , Forer Lukas , Fornage Myriam , Franceschini Nora , Fuchsberger Christian , Fullerton Stephanie M. , Germer Soren , Gladwin Mark T. , Gottlieb Daniel J. , Guo Xiuqing , Hall Michael E. , He Jiang , Heard-Costa Nancy L. , Heckbert Susan R. , Irvin Marguerite R. , Johnsen Jill M. , Johnson Andrew D. , Kaplan Robert , Kardia Sharon L. R. , Kelly Tanika , Kelly Shannon , Kenny Eimear E. , Kiel Douglas P. , Klemmer Robert , Konkle Barbara A. , Kooperberg Charles , Köttgen Anna , Lange Leslie A. , Lasky-Su Jessica , Levy Daniel , Lin Xihong , Lin Keng-Han , Liu Chunyu , Loos Ruth J. F. , Garman Lori , Gerszten Robert , Lubitz Steven A. , Lunetta Kathryn L. , Mak Angel C. Y. , Manichaikul Ani , Manning Alisa K. , Mathias Rasika A. , McManus David D. , McGarvey Stephen T. , Meigs James B. , Meyers Deborah A. , Mikulla Julie L. , Minear Mollie A. , Mitchell Braxton D. , Mohanty Sanghamitra , Montasser May E. , Montgomery Courtney , Morrison Alanna C. , Murabito Joanne M. , Natale Andrea , Natarajan Pradeep , Nelson Sarah C. , North Kari E. , O’Connell Jeffrey R. , Palmer Nicholette D. , Pankratz Nathan , Peloso Gina M. , Peyser Patricia A. , Pleiness Jacob , Post Wendy S. , Psaty Bruce M. , Rao D. C. , Redline Susan , Reiner Alexander P. , Roden Dan , Rotter Jerome I. , Ruczinski Ingo , Sarnowski Chloé , Schoenherr Sebastian , Schwartz David A. , Seo Jeong-Sun , Seshadri Sudha , Sheehan Vivien A. , Sheu Wayne H. , Shoemaker M. Benjamin , Smith Nicholas L. , Smith Jennifer A. , Sotoodehnia Nona , Stilp Adrienne M. , Tang Weihong , Taylor Kent D. , Telen Marilyn , Thornton Timothy A. , Tracy Russell P. , Van Den Berg David J. , Vasan Ramachandran S. , Viaud-Martinez Karine A. , Vrieze Scott , Weeks Daniel E. , Weir Bruce S. , Weiss Scott T. , Weng Lu-Chen , Willer Cristen J. , Zhang Yingze , Zhao Xutong , Arnett Donna K. , Ashley-Koch Allison E. , Barnes Kathleen C. , Boerwinkle Eric , Gabriel Stacey , Gibbs Richard , Rice Kenneth M. , Rich Stephen S. , Silverman Edwin K. , Qasba Pankaj , Gan Weiniu ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Abe Namiko , Almasy Laura , Ament Seth , Anderson Peter , Anugu Pramod , Applebaum-Bowden Deborah , Assimes Tim , Avramopoulos Dimitrios , Barron-Casella Emily , Beaty Terri , Beck Gerald , Becker Diane , Beitelshees Amber , Benos Takis , Bezerra Marcos , Bis Joshua , Bowler Russell , Broeckel Ulrich , Broome Jai , Bunting Karen , Bustamante Carlos , Buth Erin , Cardwell Jonathan , Carey Vincent , Carty Cara , Casaburi Richard , Castaldi Peter , Chaffin Mark , Chang Christy , Chang Yi-Cheng , Chavan Sameer , Chen Bo-Juen , Chen Wei-Min , Chuang Lee-Ming , Chung Ren-Hua , Comhair Suzy , Cornell Elaine , Crandall Carolyn , Crapo James , Curtis Jeffrey , Damcott Coleen , David Sean , Davis Colleen , Fuentes Lisa de las , DeBaun Michael , Deka Ranjan , Devine Scott , Duan Qing , Duggirala Ravi , Durda Jon Peter , Eaton Charles , Ekunwe Lynette , El Boueiz Adel , Erzurum Serpil , Farber Charles , Flickinger Matthew , Fornage Myriam , Frazar Chris , Fu Mao , Fulton Lucinda , Gao Shanshan , Gao Yan , Gass Margery , Gelb Bruce , Geng Xiaoqi Priscilla , Geraci Mark , Ghosh Auyon , Gignoux Chris , Glahn David , Gong Da-Wei , Goring Harald , Graw Sharon , Grine Daniel , Gu C. Charles , Guan Yue , Gupta Namrata , Haessler Jeff , Hawley Nicola L. , Heavner Ben , Herrington David , Hersh Craig , Hidalgo Bertha , Hixson James , Hobbs Brian , Hokanson John , Hong Elliott , Hoth Karin , Hsiung Chao Agnes , Hung Yi-Jen , Huston Haley , Hwu Chii Min , Jackson Rebecca , Jain Deepti , Jhun Min A. , Johnson Craig , Johnston Rich , Jones Kimberly , Kathiresan Sekar , Khan Alyna , Kim Wonji , Kinney Greg , Kramer Holly , Lange Christoph , Lange Ethan , Lange Leslie , Laurie Cecelia , LeBoff Meryl , Lee Jiwon , Lee Seunggeun Shawn , Lee Wen-Jane , Levine David , Lewis Joshua , Li Xiaohui , Li Yun , Lin Henry , Lin Honghuang , Lin Keng Han , Liu Simin , Liu Yongmei , Liu Yu , Luo James , Mahaney Michael , Make Barry , Manson JoAnn , Margolin Lauren , Martin Lisa , Mathai Susan , May Susanne , McArdle Patrick , McDonald Merry-Lynn , McFarland Sean , McGoldrick Daniel , McHugh Caitlin , Mei Hao , Mestroni Luisa , Min Nancy , Minster Ryan L. , Moll Matt , Moscati Arden , Musani Solomon , Mwasongwe Stanford , Mychaleckyj Josyf C. , Nadkarni Girish , Naik Rakhi , Naseri Take , Nekhai Sergei , Neltner Bonnie , Ochs-Balcom Heather , Paik David , Pankow James , Parsa Afshin , Peralta Juan Manuel , Perez Marco , Perry James , Peters Ulrike , Phillips Lawrence S. , Pollin Toni , Becker Julia Powers , Boorgula Meher Preethi , Preuss Michael , Qiao Dandi , Qin Zhaohui , Rafaels Nicholas , Raffield Laura , Rasmussen-Torvik Laura , Ratan Aakrosh , Reed Robert , Regan Elizabeth , Reupena Muagututi‘a Sefuiva , Roselli Carolina , Russell Pamela , Ruuska Sarah , Ryan Kathleen , Sabino Ester Cerdeira , Saleheen Danish , Salimi Shabnam , Salzberg Steven , Sandow Kevin , Sankaran Vijay G. , Scheller Christopher , Schmidt Ellen , Schwander Karen , Sciurba Frank , Seidman Christine , Seidman Jonathan , Sherman Stephanie L. , Shetty Aniket , Sheu Wayne Hui-Heng , Silver Brian , Smith Josh , Smith Tanja , Smoller Sylvia , Snively Beverly , Snyder Michael , Sofer Tamar , Storm Garrett , Streeten Elizabeth , Sung Yun Ju , Sylvia Jody , Szpiro Adam , Sztalryd Carole , Tang Hua , Taub Margaret , Taylor Matthew , Taylor Simeon , Threlkeld Machiko , Tinker Lesley , Tirschwell David , Tishkoff Sarah , Tiwari Hemant , Tong Catherine , Tsai Michael , Vaidya Dhananjay , VandeHaar Peter , Walker Tarik , Wallace Robert , Walts Avram , Wang Fei Fei , Wang Heming , Watson Karol , Wessel Jennifer , Williams Kayleen , Williams L. Keoki , Wilson Carla , Wu Joseph , Xu Huichun , Yanek Lisa , Yang Ivana , Yang Rongze , Zaghloul Norann , Zekavat Maryam , Zhao Snow Xueyan , Zhao Wei , Zhi Degui , Zhou Xiang , Zhu Xiaofeng , Papanicolaou George J. , Nickerson Deborah A. , Browning Sharon R. , Zody Michael C. , Zöllner Sebastian , Wilson James G. , Cupples L. Adrienne , Laurie Cathy C. , Jaquish Cashell E. , Hernandez Ryan D. , O’Connor Timothy D. , Abecasis Gonçalo R. 
Published: February 2021

AbstractThe 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. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.