Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program
Daniel Taliun(University of Michigan), Daniel Harris(University of Maryland, Baltimore), Michael D. Kessler(University of Maryland, Baltimore), Jedidiah Carlson(University of Washington), Zachary A. Szpiech(University of California, San Francisco), Raúl Torres(University of California, San Francisco), Sarah A. Gagliano Taliun(University of Michigan), André Corvelo(New York Genome Center), Stephanie M. Gogarten(University of Washington), Hyun Min Kang(University of Michigan), Achilleas Pitsillides(Boston University), Jonathon LeFaive(University of Michigan), Seung‐been Lee(University of Washington), Xiaowen Tian(University of Washington), Brian L. Browning(University of Washington Medical Center), Sayantan Das(University of Michigan), Anne‐Katrin Emde(New York Genome Center), Wayne E. Clarke(New York Genome Center), Douglas P. Loesch(University of Maryland, Baltimore), Amol C. Shetty(University of Maryland, Baltimore), Thomas W. Blackwell(University of Michigan), Quenna Wong(University of Washington), François Aguet(Broad Institute), Christine M. Albert(Massachusetts General Hospital), Álvaro Alonso(Emory University), Kristin Ardlie(Broad Institute), Stella Aslibekyan(University of Alabama at Birmingham), Paul L. Auer(Milwaukee Health Department), John Barnard(Cleveland Clinic), R. Graham Barr(Columbia University Irving Medical Center), Lewis C. Becker(Johns Hopkins University), Rebecca Beer(National Institutes of Health), Emelia J. Benjamin(Boston University), Lawrence F. Bielak(University of Michigan), John Blangero(The University of Texas Rio Grande Valley), Michael Boehnke(University of Michigan), Donald W. Bowden(Wake Forest University), Jennifer A. Brody(University of Washington), Esteban G. Burchard(University of California, San Francisco), Brian E. Cade(Brigham and Women's Hospital), James F. Casella(Johns Hopkins University), Brandon Chalazan(University of British Columbia), Yii‐Der Ida Chen(The Lundquist Institute), Michael H. Cho(Brigham and Women's Hospital), Seung Hoan Choi(Broad Institute), Mina K. Chung(Cleveland Clinic), Clary B. Clish(Broad Institute), Adolfo Correa(University of Mississippi Medical Center), Joanne E. Curran(The University of Texas Rio Grande Valley), Brian Custer(University of California, San Francisco), Dawood Darbar(University of Illinois Chicago), Michelle Daya(University of Colorado Anschutz Medical Campus), Mariza de Andrade(Mayo Clinic), Dawn L. DeMeo(Brigham and Women's Hospital), Susan K. Dutcher(James S. McDonnell Foundation), Patrick T. Ellinor(Broad Institute), Leslie S. Emery(University of Washington), Diane Fatkin(Victor Chang Cardiac Research Institute), Lukas Forer(Innsbruck Medical University), Myriam Fornage(The University of Texas Health Science Center at Houston), Nora Franceschini(University of North Carolina at Chapel Hill), Christian Fuchsberger(Eurac Research), Stephanie M. Fullerton(University of Washington), Søren Germer(New York Genome Center), Mark T. Gladwin(University of Pittsburgh), Daniel J. Gottlieb(Brigham and Women's Hospital), Xiuqing Guo(The Lundquist Institute), Michael E. Hall(University of Mississippi Medical Center), Jiang He(Tulane University), Nancy L. Heard‐Costa(Boston University), Susan R. Heckbert(University of Washington), Marguerite R. Irvin(University of Alabama at Birmingham), Jill M. Johnsen(University of Washington), Andrew D. Johnson(National Institutes of Health), Sharon L. R. Kardia(University of Michigan), Tanika N. Kelly(Tulane University), Shannon Kelly(Pacific Research Institute), Eimear E. Kenny(Icahn School of Medicine at Mount Sinai), Douglas P. Kiel(Beth Israel Deaconess Medical Center), Robert Klemmer(University of Michigan), Barbara A. Konkle(University of Washington), Charles Kooperberg(Fred Hutch Cancer Center), Anna Köttgen(Johns Hopkins University), Leslie A. Lange(University of Colorado Denver), Jessica Lasky‐Su(Brigham and Women's Hospital), Daniel Levy(Boston University), Xihong Lin(Harvard University), Keng‐Han Lin(University of Michigan), Chunyu Liu(Boston University), Ruth J. F. Loos(Child Health and Development Institute), Lori Garman(Oklahoma Medical Research Foundation), Robert E. Gerszten(Beth Israel Deaconess Medical Center), Steven A. Lubitz(Massachusetts General Hospital), Kathryn L. Lunetta(Boston University), Angel C. Y. Mak(University of California, San Francisco), Ani Manichaikul(University of Virginia), Alisa K. Manning(Broad Institute), Rasika A. Mathias(Johns Hopkins University), David D. McManus(University of Massachusetts Chan Medical School), Stephen T. McGarvey(Brown University), James B. Meigs(Broad Institute), Deborah A. Meyers(University of Arizona), Julie Mikulla(National Institutes of Health), Mollie Minear(National Institutes of Health), Braxton D. Mitchell(University of Maryland, Baltimore), Sanghamitra Mohanty(Dell Children's Medical Center of Central Texas), May E. Montasser(University of Maryland, Baltimore), Courtney G. Montgomery(Oklahoma Medical Research Foundation), Alanna C. Morrison(New York Genome Center), Joanne M. Murabito(Boston University), Andrea Natale(Dell Children's Medical Center of Central Texas), Pradeep Natarajan(Broad Institute), Sarah C. Nelson(University of Washington), Kari E. North(University of North Carolina at Chapel Hill), Jeffrey R. O’Connell(University of Maryland, Baltimore), Nicholette D. Palmer(Wake Forest University), Nathan Pankratz(University of Minnesota), Gina M. Peloso(Boston University), Patricia A. Peyser(University of Michigan), Wendy S. Post(Johns Hopkins University), Bruce M. Psaty(Kaiser Permanente Washington Health Research Institute), D. C. Rao(Washington University in St. Louis), Susan Redline(Brigham and Women's Hospital), Alex P. Reiner(University of Washington), Dan M. Roden(Broad Institute), Jerome I. Rotter(The Lundquist Institute), Ingo Ruczinski(Johns Hopkins University), Chloé Sarnowski(Boston University), Sebastian Schoenherr(Innsbruck Medical University), Jeong‐Sun Seo(Seoul National University Bundang Hospital), Sudha Seshadri(The University of Texas at San Antonio Health Science Center), Vivien Sheehan(Boston University), M. Benjamin Shoemaker(Broad Institute), Albert V. Smith(University of Michigan), Nicholas L. Smith(University of Puget Sound), Jennifer A. Smith(University of Michigan), Nona Sotoodehnia(Boston University), Adrienne M. Stilp(University of Washington), Weihong Tang(Boston University), Kent D. Taylor(The Lundquist Institute), Marilyn J. Telen(Boston University), Timothy A. Thornton(University of Washington), Russell P. Tracy(Boston University), David Van Den Berg(Boston University), Ramachandran S. Vasan(Boston University), Karine A. Viaud‐Martinez(Illumina (United States)), Scott Vrieze(Boston University), Daniel E. Weeks(University of Pittsburgh), Bruce S. Weir(University of Washington), Scott T. Weiss(Brigham and Women's Hospital), Lu‐Chen Weng(Massachusetts General Hospital), Cristen J. Willer(University of Michigan), Yingze Zhang(University of Pittsburgh), Xutong Zhao(Harvard University), Donna K. Arnett(Brigham and Women's Hospital), Allison E. Ashley‐Koch(Johns Hopkins University), Kathleen C. Barnes(University of Colorado Anschutz Medical Campus), Eric Boerwinkle(Baylor College of Medicine), Stacey Gabriel(Broad Institute), Richard A. Gibbs(Baylor College of Medicine), Kenneth Rice(University of Washington), Stephen S. Rich(University of Virginia), Edwin K. Silverman(Brigham and Women's Hospital), Pankaj Qasba(National Institutes of Health), Weiniu Gan(National Institutes of Health), Trans-Omics for Precision Medicine (TOPMed) Program, TOPMed Population Genetics Working Group(National Institutes of Health), George Papanicolaou(University of Washington), Deborah A. Nickerson(University of Washington), Sharon R. Browning(University of Washington), Michael C. Zody(University of Michigan), Sebastian Zöllner(University of Mississippi Medical Center), James G. Wilson(Broad Institute), L. Adrienne Cupples(University of Washington), Cathy C. Laurie(National Institutes of Health), Cashell E. Jaquish(University of California, San Francisco), Ryan D. Hernandez(University of Maryland, Baltimore), Timothy D. O’Connor(University of Michigan), Gonçalo R. Abecasis(Statistical Service)
Cited by 423Open Access
Abstract
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.
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