PT  - JOURNAL ARTICLE
AU  - Zhong Ren
AU  - Gundula Povysil
AU  - David B. Goldstein
TI  - ATAV: a comprehensive platform for population-scale genomic analyses
AID  - 10.1101/2020.06.08.136507
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.08.136507
4099  - http://biorxiv.org/content/early/2020/09/17/2020.06.08.136507.short
4100  - http://biorxiv.org/content/early/2020/09/17/2020.06.08.136507.full
AB  - Background A common approach for sequencing studies is to do joint-calling and store variants of all samples in a single file. If new samples keep being added or controls are re-used for several studies, the cost and time required to perform joint-calling for each analysis can become prohibitive.Results We present ATAV, an analysis platform for large-scale whole-exome and whole-genome sequencing projects. ATAV stores variant and per site coverage data for all samples in a centralized database, which is efficiently queried by ATAV to support diagnostic analyses for trios and singletons, as well as rare-variant collapsing analyses for finding disease associations in complex diseases. Runtime logs ensure full reproducibility and the modularized ATAV framework makes it extensible to continuous development. Besides helping with the identification of disease-causing variants for a range of diseases, ATAV has also enabled the discovery of disease-genes by rare-variant collapsing on datasets containing more than 20,000 samples. Analyses to date have been performed on data of more than 110,000 individuals demonstrating the scalability of the framework.The ATAV data browser (http://atavdb.org/) is a web-based interface that allows users to easily access variant-level data directly from the database. Summary-level data for more than 40,000 samples can be queried by the general public representing a mix of cases and controls of diverse ancestries. Users have access to phenotype categories of variant carriers, as well as predicted ancestry, gender, and quality metrics. In contrast to many other platforms, the data browser is able to show data of newly-added samples in real-time and is therefore evolving rapidly as more and more samples are sequenced.Conclusions Since all code is freely available on GitHub, ATAV can easily be used by other groups to build up their own platform, database, and user interface. In addition to that users can query one of the largest variant databases for patients sequenced at a tertiary care center and look up their own genes or variants of interest.Competing Interest StatementD.B.G. is a founder of and holds equity in Praxis, holds equity in Q-State Biosciences, serves as a consultant to AstraZeneca, and has received research support from Janssen, Gilead, Biogen, AstraZeneca, and Union Chimique Belge (UCB). Z.R. and G.P. declare no competing interests.List of abbreviationsVCFVariant Call FormatBAMBinary Alignment MapgnomADThe Genome Aggregation DatabaseRVISResidual Variation Intolerance ScoreATAVDBATAV DatabaseIGMInstitute for Genomic MedicineClinEffClinical Variant Annotations SoftwareExACThe Exome Aggregation ConsortiumGERPGenomic Evolutionary Rate ProfilingTraPThe Transcript-inferred PathogenicityLIMBRThe Localized Intolerance Model using Bayesian RegressionMTRThe missense tolerance ratioHGMDThe Human Gene Mutation DatabaseOMIMOnline Mendelian Inheritance in ManSQLStructured Query LanguagePolyPhenPolymorphism PhenotypingQCQuality ControlQVsQualifying VariantsQUALquality scoreGQgenotype quality scoreQDquality by depth scoreMQmapping quality scoreVQSLODvariant quality score log-oddsMAFMinor Allele FrequenciesHDFSHadoop Distributed File System