Structural variation across 138,134 samples in the TOPMed consortium

Abstract

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hematologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.

Comprehensive and accurate genome analysis at scale using DRAGEN accelerated algorithms

“…We next investigated how many of these variants have been identified previously 19,56 . For this task we used ICA to annotate variant intersections to 1kGP, gnomAD and TOPMed.…”

“…For variant annotation, we used the merged variant file that is normalized and the multi-allelic sites split into different lines. We extracted the variants for 2,504 unrelated samples and then the annotation was done using Illumina Connected Annotations (ICA) from three different sources: gnomAD, 1kGP and TOPMed 19,84 . The novel variants are the ones with counts for all these four sources marked as zero in the annotated VCF file and the remaining i.e., with count > 0 for at least one source is considered to be known variant.…”

“…This motivates multiple large scale studies (e.g. Centers for Common Disease Genomics (CCDG) 18 , Trans-Omics for Precision Medicine (TOPMed) 19 , All of US (AoU), UK Biobank (UKBB)) focusing on Illumina sequencing which substantiates short reads’ role as the workhorse of genomics and genetics. It also requires a scalable and unified software framework to comprehensively identify all variant types (SNV, indel, SV, and repeat expansion), which has not been realized so far 6 .…”

SVarp: pangenome-based structural variant discovery

“…While most studies have focussed on single nucleotide polymorphisms (SNPs) and small insertions and deletions (Indels) in the past, there is an increasing interest also in structural variants (SVs), which are an important contributor to human phenotypes in general and to genetic diseases in particular [6][7][8][9][10][11][12]. They are known to affect more nucleotides and have higher impact on gene functions compared to SNPs or Indels [13].…”

SEAD: an augmented reference panel with 22,134 haplotypes boosts the rare variants imputation and GWAS analysis in Asian population

“…As many rare and low-frequency variants associated with diseases tend to be population-specific (11), an increasing number of human genome projects are focusing on specific populations to provide population-specific reference panels. However, most of the whole-genome sequencing (WGS) efforts were carried out in European-descent individuals, such as the GoNL project (the Genome of the Netherlands project, n=769) (12), UK10K project (∼4,000 WGS and ∼6,000 whole exome sequencing samples in UK)(13, 14) and the TOPMed program (Trans-Omics for Precision Medicine, n=∼138,000) (15). These efforts have enabled the provision of a large-scale combined reference panel for the European population, such as the HRC panel (Haplotype Reference Consortium, n=32,470) (16).…”