Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects

Regier, Allison; Farjoun, Yossi; Larson, David E.; Krasheninina, Olga; Kang, Hyun Min; Howrigan, Daniel P.; Chen, Bo Juen; Kher, Manisha; Banks, Eric; Ames, Darren; English, Adam C.; Li, Heng; Xing, Jinchuan; Zhang, Yeting; Matise, Tara C.; Abecasis, Gonçalo R.; Salerno, Will; Zody, Michael C.; Neale, Benjamin M.; Hall, Ira M.

doi:10.1038/s41467-018-06159-4

Cited by 175 publications

(101 citation statements)

References 21 publications

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“…Sequence data processing was performed periodically to produce genotype data "Freezes" that include all samples available at a given time. All sequence was remapped using BWA-MEM 83 to the hs38DH 1000 Genomes build 38 human genome reference including decoy sequences, following the protocol 84 published by Regier et al 2018 85 . Variant discovery and genotype calling was performed jointly, across TOPMed Parent studies, for all samples in a given Freeze using the GotCloud 86 pipeline.…”

Section: Sequence Data Processing and Variant Callingmentioning

confidence: 99%

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

Taliun¹,

Harris²,

Kessler³

et al. 2019

Preprint

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463

653

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Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

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Section: Sequence Data Processing and Variant Callingmentioning

confidence: 99%

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

Taliun¹,

Harris²,

Kessler³

et al. 2019

Preprint

Self Cite

463

653

View full text Add to dashboard Cite

show abstract

“…Using the pipeline from the Centers for the Common Disease Genomics project (Regier et al, 2018), FASTQ reads were aligned to the GRCh38 reference from the 1000 Genomes Project using BWA-MEM version 0.7.15. Reads were sorted and duplicates were removed with Picard, version 2.17.5.; base quality score recalibration was then performed with the Genome Analysis Toolkit (GATK), v3.8-0-ge9d806836.…”

Section: Wgs Variant Callingmentioning

confidence: 99%

Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex

et al. 2020

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All available non-identifying information was recorded for each specimen in Table S1. In total, 176 postmortem brain specimens (104 male, 72 female; postmortem interval of 21.7 ± 15.9 (mean ± SD) hours and pH, 6.41 ± 0.35) ranging in age from 6 post-conception weeks (PCW) to 20 postnatal years (PY) ( Figure 1 and Table S1) were included in this study. Fetal age was extrapolated based on the date of the mother's last menstruation, characteristics of the fetus noted upon ultrasonography scanning, foot length of the fetus, and visual inspection. The postmortem interval (PMI) was defined as hours between time of death and time when tissue samples were frozen. METHOD DETAILS Tissue dissectionTissue was dissected as described previously (Kang et al. 2011). Samples collected from 6 -9 PCW specimens contained the entire thickness of the cerebral wall. Samples collected from 12 -22 PCW specimens contained the cortical plate. Samples from 35 PCW -20 PY specimens were dissected such that the entire gray matter (layer 1-6) and part of the underlying subplate (4 -12 postnatal months) or white matter (1 -20 PY) were collected. RNA extraction and quality assessmentTotal RNA was extracted using mirVana kit (Ambion) with some modifications, as given in the following text, to the manufacturer's protocol, as described below. Each tissue sample was

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“…The UK Biobank (UKB) is a large cohort study consists of approximately half a million participants aged between 40 and 69 at recruitment, with extensive phenotypic records 18 65 and Functionally Equivalent (FE) 66 .…”

Section: Uk Biobank Datamentioning

confidence: 99%

A resource-efficient tool for mixed model association analysis of large-scale data

Jiang

Zheng

et al. 2019

Preprint

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The genome-wide association study (GWAS) has been widely used as an experimental design to detect associations between genetic variants and a phenotype. Two major confounding factors, population stratification and relatedness, could potentially lead to inflated GWAS test-statistics and thereby spurious associations. Mixed linear model (MLM)-based approaches can be used to account for sample structure. However, genome-wide association (GWA) analyses in biobank samples such as the UK Biobank (UKB) often exceed the capability of most existing MLM-based tools especially if the number of traits is large. Here, we developed an MLM-based tool (called fastGWA) that controls for population stratification by principal components and relatedness by a sparse genetic relationship matrix for GWA analyses of biobank-scale data. We demonstrated by extensive simulations that fastGWA is reliable, robust and highly resource-efficient. We then applied fastGWA to 2,173 traits on 456,422 array-genotyped and imputed individuals and 2,048 traits on 46,191 whole-exome-sequenced individuals in the UKB.

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Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects

Cited by 175 publications

References 21 publications

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

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

Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex

A resource-efficient tool for mixed model association analysis of large-scale data

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