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

• Authors: Stephanie Sherman, Emory University; Alvaro Alonso, Emory University; Zhaohui Qin, Emory University; Adolfo Correa, Emory University; Vivien Sheehan, Emory University; D Taliun, University of Michigan; DN Harris, Univ Maryland; MD Kessler, Univ Maryland; J Carlson, University of Michigan; ZA Szpiech, Pennsylvania State University; R Torres, University of California San Francisco; SAG Taliun, University of Michigan; A Corvelo, New York Genome Ctr; SM Gogarten, University of Washington; HM Kang, University of Michigan; AN Pitsillides, Boston University; J LeFaive, University of Michigan; S-B Lee, University of Washington; X Tian, University of Washington; BL Browning, University of Washington; S Das, University of Michigan; A-K Emde, New York Genome Ctr; WE Clarke, New York Genome Ctr; DP Loesch, Univ Maryland; AC Shetty, Univ Maryland; TW Blackwell, University of Michigan; A Smith, University of Michigan; Q Wong, University of Washington; X Liu, University of South Florida; MP Conomos, University of Washington; DM Bobo, Icahn Sch Med Mt Sinai; F Aguet, Broad Inst MIT & Harvard; C Albert, Massachusetts General Hospital; KG Ardlie, Broad Inst MIT & Harvard; DE Arking, Johns Hopkins University; S Aslibekyan, University of Alabama Birmingham; PL Auer, Univ Wisconsin; J Barnard, Cleveland Clin; RG Barr, Columbia University; L Barwick, Emmes Corporation; LC Becker, Johns Hopkins University; RL Beer, NHLBI; EJ Benjamin, Boston University; LF Bielak, University of Michigan; J Blangero, University of Texas Rio Grande Valley; M Boehnke, University of Michigan; DW Bowden, Wake Forest Sch Med; JA Brody, University of Washington; EG Burchard, University of California San Francisco; BE Cade, Harvard Medical School; JF Casella, Johns Hopkins University; B Chalazan, University of British Columbia; D Chasman, Brigham & Womens Hosp; Y-DI Chen, Harbor UCLA Med Ctr; MH Cho, Brigham & Womens Hosp; SH Choi, Broad Inst MIT & Harvard; MK Chung, Cleveland Clin; CB Clish, Broad Inst MIT & Harvard; JE Curran, University of Texas Rio Grande Valley; B Custer, Vitalant Research Institute; D Darbar, Univ Illinois; M Daya, Univ Colorado; M de Andrade, Mayo Clinic; DL DeMeo, Brigham & Womens Hosp; SK Dutcher, Washington Univ; PT Ellinor, Broad Inst MIT & Harvard; LS Emery, University of Washington; C Eng, University of California San Francisco; D Fatkin, Victor Chang Cardiac Research Institute; T Fingerlin, Natl Jewish Hlth; L Forer, Medical University of Innsbruck; M Fornage, Univ Texas Hlth Sci Ctr Houston; N Franceschini, University of North Carolina; C Fuchsberger, University of Michigan; SM Fullerton, University of Washington; S Germer, New York Genome Ctr; MT Gladwin, University of Pittsburgh; DJ Gottlieb, VA Boston Healthcare System; X Guo, Harbor UCLA Med Ctr; ME Hall, University of Mississippi; J He, Tulane University; NL Heard-Costa, Framingham Heart Dis Epidemiol Study; SR Heckbert, University of Washington; MR Irvin, University of Alabama Birmingham; JM Johnsen, University of Washington; AD Johnson, Framingham Heart Dis Epidemiol Study; R Kaplan, Albert Einstein Coll Med; SLR Kardia, University of Michigan; T Kelly, Tulane University; S Kelly, Vitalant Research Institute; EE Kenny, Icahn Sch Med Mt Sinai; DP Kiel, Broad Inst MIT & Harvard; R Klemmer, University of Michigan; BA Konkle, University of Washington; C Kooperberg, Fred Hutchinson Canc Res Ctr; A Kottgen, Johns Hopkins University; LA Lange, Univ Colorado Denver; J Lasky-Su, Harvard Medical School; D Levy, Boston University; X Lin, Harvard University; K-H Lin, University of Michigan; C Liu, Boston University; RJF Loos, Icahn Sch Med Mt Sinai; L Garman, Oklahoma Med Res Fdn; R Gerszten, Beth Israel Deaconess Med Ctr; SA Lubitz, Massachusetts General Hospital; KL Lunetta, Boston University; ACY Mak, University of California San Francisco; A Manichaikul, University of Virginia; AK Manning, Harvard Medical School; RA Mathias, Johns Hopkins University; DD McManus, Univ Massachusetts; ST McGarvey, Brown University; JB Meigs, Harvard Medical School; DA Meyers, University of Arizona; JL Mikulla, NHLBI; MA Minear, NHLBI; BD Mitchell, Univ Maryland; S Mohanty, St Davids Med Ctr; ME Montasser, Univ Maryland; C Montgomery, Oklahoma Med Res Fdn; AC Morrison, Univ Texas Hlth Sci Ctr Houston; JM Murabito, Boston University; A Natale, St Davids Med Ctr; P Natarajan, Harvard Medical School; SC Nelson, University of Washington; KE North, University of North Carolina; JR O'Connell, Univ Maryland; ND Palmer, Wake Forest Sch Med; N Pankratz, Univ Minnesota; GM Peloso, Boston University; PA Peyser, University of Michigan; J Pleiness, University of Michigan; WS Post, Johns Hopkins University; BM Psaty, University of Washington; DC Rao, Washington Univ; S Redline, Harvard Medical School; AP Reiner, University of Washington; D Roden, Vanderbilt University; J Rotter, Harbor UCLA Med Ctr; I Ruczinski, Johns Hopkins Bloomberg Sch Publ Hlth; C Sarnowski, Boston University; S Schoenherr, Medical University of Innsbruck; DA Schwartz, Univ Colorado; J-S Seo, Seoul Natl Univ; S Seshadri, Framingham Heart Dis Epidemiol Study; WH Sheu, Taichung Vet Gen Hosp Taiwan; MB Shoemaker, Vanderbilt University; NL Smith, University of Washington; JA Smith, University of Michigan; N Sotoodehnia, University of Washington; AM Stilp, University of Washington; W Tang, Univ Minnesota; KD Taylor, Harbor UCLA Med Ctr; M Telen, Duke University; TA Thornton, University of Washington; RP Tracy, University of Vermont; DJ Van den Berg, University of Southern California; RS Vasan, Boston University; KA Viaud-Martinez, Illumina Inc; S Vrieze, Univ Minnesota; DE Weeks, University of Pittsburgh; BS Weir, University of Washington; ST Weiss, Harvard Medical School; L-C Weng, Massachusetts General Hospital; CJ Willer, University of Michigan; Y Zhang, University of Pittsburgh; X Zhao, University of Michigan; DK Arnett, University of Kentucky; AE Ashley-Koch, Duke University; KC Barnes, Univ Colorado; E Boerwinkle, Univ Texas Hlth Sci Ctr Houston; S Gabriel, Broad Inst MIT & Harvard; R Gibbs, Baylor College of Medicine; KM Rice, University of Washington; SS Rich, University of Virginia; EK Silverman, Brigham & Womens Hosp; P Qasba, NHLBI; W Gan, NHLBI; GJ Papanicolaou, NHLBI; DA Nickerson, University of Washington; SR Browning, University of Washington; MC Zody, New York Genome Ctr; S Zollner, University of Michigan; JG Wilson, University of Mississippi; LA Cupples, Boston University; CC Laurie, University of Washington; CE Jaquish, NHLBI; RD Hernandez, University of California San Francisco; TD O'Connor, Univ Maryland; GR Abecasis, University of Michigan
• Journal Title: NATURE
• Volume: Volume 590, Number 7845
• Publisher: NATURE RESEARCH | 2021-02-11, Pages 290-299
• Type of Work: Article
• Publisher DOI: http://doi.org/10.1038/s41586-021-03205-y
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CYTOCHROME-P450 2D6; GENETIC-VARIATION; RARE VARIANTS; DNA-SEQUENCE; HUMAN-LIVER; R PACKAGE; INFERENCE; FRAMEWORK; EFFICIENT; PROTEIN

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. 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%.