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

Nature. 2021 Feb;590(7845):290-299. doi: 10.1038/s41586-021-03205-y. Epub 2021 Feb 10.

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%.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cytochrome P-450 CYP2D6 / genetics
  • Genetic Variation / genetics*
  • Genome, Human / genetics*
  • Genomics*
  • Haplotypes / genetics
  • 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* / standards
  • Quality Control
  • Sample Size
  • United States
  • Whole Genome Sequencing / standards

Substances

  • Cytochrome P-450 CYP2D6