Title | Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Taliun, D, Harris, DN, Kessler, MD, Carlson, J, Szpiech, ZA, Torres, R, Taliun, SAGagliano, Corvelo, A, Gogarten, SM, Kang, HMin, Pitsillides, AN, LeFaive, J, Lee, S-B, Tian, X, Browning, BL, Das, S, Emde, A-K, Clarke, WE, Loesch, DP, Shetty, AC, Blackwell, TW, Smith, AV, Wong, Q, Liu, X, Conomos, MP, Bobo, DM, Aguet, F, Albert, C, Alonso, A, Ardlie, KG, Arking, DE, Aslibekyan, S, Auer, PL, Barnard, J, R Barr, G, Barwick, L, Becker, LC, Beer, RL, Benjamin, EJ, Bielak, LF, Blangero, J, Boehnke, M, Bowden, DW, Brody, JA, Burchard, EG, Cade, BE, Casella, JF, Chalazan, B, Chasman, DI, Chen, Y-DIda, Cho, MH, Choi, SHoan, Chung, MK, Clish, CB, Correa, A, Curran, JE, Custer, B, Darbar, D, Daya, M, de Andrade, M, DeMeo, DL, Dutcher, SK, Ellinor, PT, Emery, LS, Eng, C, Fatkin, D, Fingerlin, T, Forer, L, Fornage, M, Franceschini, N, Fuchsberger, C, Fullerton, SM, Germer, S, Gladwin, MT, Gottlieb, DJ, Guo, X, Hall, ME, He, J, Heard-Costa, NL, Heckbert, SR, Irvin, MR, Johnsen, JM, Johnson, AD, Kaplan, R, Kardia, SLR, Kelly, T, Kelly, S, Kenny, EE, Kiel, DP, Klemmer, R, Konkle, BA, Kooperberg, C, Köttgen, A, Lange, LA, Lasky-Su, J, Levy, D, Lin, X, Lin, K-H, Liu, C, Loos, RJF, Garman, L, Gerszten, R, Lubitz, SA, Lunetta, KL, C Y Mak, A, Manichaikul, A, Manning, AK, Mathias, RA, McManus, DD, McGarvey, ST, Meigs, JB, Meyers, DA, Mikulla, JL, Minear, MA, Mitchell, BD, Mohanty, S, Montasser, ME, Montgomery, C, Morrison, AC, Murabito, JM, Natale, A, Natarajan, P, Nelson, SC, North, KE, O'Connell, JR, Palmer, ND, Pankratz, N, Peloso, GM, Peyser, PA, Pleiness, J, Post, WS, Psaty, BM, Rao, DC, Redline, S, Reiner, AP, Roden, D, Rotter, JI, Ruczinski, I, Sarnowski, C, Schoenherr, S, Schwartz, DA, Seo, J-S, Seshadri, S, Sheehan, VA, Sheu, WH, M Shoemaker, B, Smith, NL, Smith, JA, Sotoodehnia, N, Stilp, AM, Tang, W, Taylor, KD, Telen, M, Thornton, TA, Tracy, RP, Van Den Berg, DJ, Vasan, RS, Viaud-Martinez, KA, Vrieze, S, Weeks, DE, Weir, BS, Weiss, ST, Weng, L-C, Willer, CJ, Zhang, Y, Zhao, X, Arnett, DK, Ashley-Koch, AE, Barnes, KC, Boerwinkle, E, Gabriel, S, Gibbs, RA, Rice, KM, Rich, SS, Silverman, EK, Qasba, P, Gan, W, Papanicolaou, GJ, Nickerson, DA, Browning, SR, Zody, MC, Zöllner, S, Wilson, JG, L Cupples, A, Laurie, CC, Jaquish, CE, Hernandez, RD, O'Connor, TD, Abecasis, GR |
Corporate Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium |
Journal | Nature |
Volume | 590 |
Issue | 7845 |
Pagination | 290-299 |
Date Published | 2021 Feb |
ISSN | 1476-4687 |
Keywords | Cytochrome P-450 CYP2D6, Genetic Variation, Genome, Human, Genomics, Haplotypes, Heterozygote, Humans, INDEL Mutation, Loss of Function Mutation, Mutagenesis, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Population Density, Precision Medicine, Quality Control, Sample Size, United States, Whole Genome Sequencing |
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). 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%. |
DOI | 10.1038/s41586-021-03205-y |
Alternate Journal | Nature |
PubMed ID | 33568819 |
PubMed Central ID | PMC7875770 |
Grant List | R35 HG010692 / HG / NHGRI NIH HHS / United States P30 ES010126 / ES / NIEHS NIH HHS / United States P50 HL118006 / HL / NHLBI NIH HHS / United States T32 HG000040 / HG / NHGRI NIH HHS / United States R01 HL090620 / HL / NHLBI NIH HHS / United States K08 HL141601 / HL / NHLBI NIH HHS / United States HHSN268201800001C / HL / NHLBI NIH HHS / United States K24 HL148521 / HL / NHLBI NIH HHS / United States R01 HL111314 / HL / NHLBI NIH HHS / United States R01 AI132476 / AI / NIAID NIH HHS / United States R01 HL117626 / HL / NHLBI NIH HHS / United States R01 HL131565 / HL / NHLBI NIH HHS / United States R01 DA044283 / DA / NIDA NIH HHS / United States R01 HL123915 / HL / NHLBI NIH HHS / United States R01 HL120393 / HL / NHLBI NIH HHS / United States R03 HL141439 / HL / NHLBI NIH HHS / United States K01 AG059898 / AG / NIA NIH HHS / United States R01 HL155742 / HL / NHLBI NIH HHS / United States U01 HL120393 / HL / NHLBI NIH HHS / United States R01 DK117445 / DK / NIDDK NIH HHS / United States UH3 HL151865 / HL / NHLBI NIH HHS / United States R01 HL163972 / HL / NHLBI NIH HHS / United States R01 AR072199 / AR / NIAMS NIH HHS / United States R01 HL142711 / HL / NHLBI NIH HHS / United States I01 BX005295 / BX / BLRD VA / United States R01 HL113326 / HL / NHLBI NIH HHS / United States U01 HL137162 / HL / NHLBI NIH HHS / United States R01 HG005701 / HG / NHGRI NIH HHS / United States T32 HL007085 / HL / NHLBI NIH HHS / United States R01 DA037904 / DA / NIDA NIH HHS / United States R21 HL123677 / HL / NHLBI NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States R03 HL154284 / HL / NHLBI NIH HHS / United States R01 MD012765 / MD / NIMHD NIH HHS / United States U01 CA182913 / CA / NCI NIH HHS / United States U01 HG009088 / HG / NHGRI NIH HHS / United States UM1 DK078616 / DK / NIDDK NIH HHS / United States UG3 HL151865 / HL / NHLBI NIH HHS / United States R01 HL149836 / HL / NHLBI NIH HHS / United States K01 HL135405 / HL / NHLBI NIH HHS / United States |
Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.
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