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

TLDR

TOPMed seeks to elucidate the genetic architecture of heart, lung, blood, and sleep disorders, and its extensive catalogue of rare and noncoding variants offers insights into mutational processes, human evolution, and phenotypic variation. This study describes TOPMed’s goals and design, the resources available, and early insights derived from the sequence data. Initial phases performed whole‑genome sequencing on diverse individuals with rich phenotypic data, and the program provides a variant browser, genotype‑imputation server, and dbGaP‑accessible genomic and phenotypic datasets. In 53,831 samples, over 400 million variants were identified—97 % with frequencies below 1 % and 46 % singletons—along with additional novel variants from unmapped‑read assembly, and combining TOPMed haplotypes with modern imputation extends GWAS power to variants as rare as 0.01 %.

Abstract

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%.