Dataset Information

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

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%.

SUBMITTER: Taliun D

PROVIDER: S-EPMC7875770 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Taliun Daniel D Harris Daniel N DN Kessler Michael D MD Carlson Jedidiah J Szpiech Zachary A ZA Torres Raul R Taliun Sarah A Gagliano SAG Corvelo André A Gogarten Stephanie M SM Kang Hyun Min HM Pitsillides Achilleas N AN LeFaive Jonathon J Lee Seung-Been SB Tian Xiaowen X Browning Brian L BL Das Sayantan S Emde Anne-Katrin AK Clarke Wayne E WE Loesch Douglas P DP Shetty Amol C AC Blackwell Thomas W TW Smith Albert V AV Wong Quenna Q Liu Xiaoming X Conomos Matthew P MP Bobo Dean M DM Aguet François F Albert Christine C Alonso Alvaro A Ardlie Kristin G KG Arking Dan E DE Aslibekyan Stella S Auer Paul L PL Barnard John J Barr R Graham RG Barwick Lucas L Becker Lewis C LC Beer Rebecca L RL Benjamin Emelia J EJ Bielak Lawrence F LF Blangero John J Boehnke Michael M Bowden Donald W DW Brody Jennifer A JA Burchard Esteban G EG Cade Brian E BE Casella James F JF Chalazan Brandon B Chasman Daniel I DI Chen Yii-Der Ida YI Cho Michael H MH Choi Seung Hoan SH Chung Mina K MK Clish Clary B CB Correa Adolfo A Curran Joanne E JE Custer Brian B Darbar Dawood D Daya Michelle M de Andrade Mariza M DeMeo Dawn L DL Dutcher Susan K SK Ellinor Patrick T PT Emery Leslie S LS Eng Celeste C Fatkin Diane D Fingerlin Tasha T Forer Lukas L Fornage Myriam M Franceschini Nora N Fuchsberger Christian C Fullerton Stephanie M SM Germer Soren S Gladwin Mark T MT Gottlieb Daniel J DJ Guo Xiuqing X Hall Michael E ME He Jiang J Heard-Costa Nancy L NL Heckbert Susan R SR Irvin Marguerite R MR Johnsen Jill M JM Johnson Andrew D AD Kaplan Robert R Kardia Sharon L R SLR Kelly Tanika T Kelly Shannon S Kenny Eimear E EE Kiel Douglas P DP Klemmer Robert R Konkle Barbara A BA Kooperberg Charles C Köttgen Anna A Lange Leslie A LA Lasky-Su Jessica J Levy Daniel D Lin Xihong X Lin Keng-Han KH Liu Chunyu C Loos Ruth J F RJF Garman Lori L Gerszten Robert R Lubitz Steven A SA Lunetta Kathryn L KL Mak Angel C Y ACY Manichaikul Ani A Manning Alisa K AK Mathias Rasika A RA McManus David D DD McGarvey Stephen T ST Meigs James B JB Meyers Deborah A DA Mikulla Julie L JL Minear Mollie A MA Mitchell Braxton D BD Mohanty Sanghamitra S Montasser May E ME Montgomery Courtney C Morrison Alanna C AC Murabito Joanne M JM Natale Andrea A Natarajan Pradeep P Nelson Sarah C SC North Kari E KE O'Connell Jeffrey R JR Palmer Nicholette D ND Pankratz Nathan N Peloso Gina M GM Peyser Patricia A PA Pleiness Jacob J Post Wendy S WS Psaty Bruce M BM Rao D C DC Redline Susan S Reiner Alexander P AP Roden Dan D Rotter Jerome I JI Ruczinski Ingo I Sarnowski Chloé C Schoenherr Sebastian S Schwartz David A DA Seo Jeong-Sun JS Seshadri Sudha S Sheehan Vivien A VA Sheu Wayne H WH Shoemaker M Benjamin MB Smith Nicholas L NL Smith Jennifer A JA Sotoodehnia Nona N Stilp Adrienne M AM Tang Weihong W Taylor Kent D KD Telen Marilyn M Thornton Timothy A TA Tracy Russell P RP Van Den Berg David J DJ Vasan Ramachandran S RS Viaud-Martinez Karine A KA Vrieze Scott S Weeks Daniel E DE Weir Bruce S BS Weiss Scott T ST Weng Lu-Chen LC Willer Cristen J CJ Zhang Yingze Y Zhao Xutong X Arnett Donna K DK Ashley-Koch Allison E AE Barnes Kathleen C KC Boerwinkle Eric E Gabriel Stacey S Gibbs Richard R Rice Kenneth M KM Rich Stephen S SS Silverman Edwin K EK Qasba Pankaj P Gan Weiniu W Papanicolaou George J GJ Nickerson Deborah A DA Browning Sharon R SR Zody Michael C MC Zöllner Sebastian S Wilson James G JG Cupples L Adrienne LA Laurie Cathy C CC Jaquish Cashell E CE Hernandez Ryan D RD O'Connor Timothy D TD Abecasis Gonçalo R GR

Nature 20210210 7845

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 th ...[more]

PMID: 33568819

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Project description:Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

Dataset Information

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

Publications

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

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