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. , Wong Quenna , Aguet François , Albert Christine , Alonso Alvaro , Ardlie Kristin G. , Aslibekyan Stella , Auer Paul L. , Barnard John , Barr R. Graham , 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 , 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 , Andrade Mariza de , DeMeo Dawn L. , Dutcher Susan K. , Ellinor Patrick T. , Emery Leslie S. , Fatkin Diane , 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. , 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 , 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. , 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 , Seo Jeong-Sun , Seshadri Sudha , Sheehan Vivien A. , Shoemaker M. Benjamin , Smith Albert V. , Smith Nicholas L. , Smith Jennifer A. , Sotoodehnia Nona , Stilp Adrienne M. , Tang Weihong , Taylor Kent D. , Telen Marilyn , Thornton Timothy A. , Tracy Russell P. , Berg David J. Van Den , 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 , Qasba Pankaj , Gan Weiniu ,   Trans-Omics for Precision Medicine (TOPMed) Program, TOPMed Population Genetics Working Group, 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: March 2019

Summary paragraph

The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.