RT Journal Article
SR Electronic
T1 Quality Control and Integration of Genotypes from Two Calling Pipelines for Whole Genome Sequence Data in the Alzheimer’s Disease Sequencing Project
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 318857
DO 10.1101/318857
A1 Adam C. Naj
A1 Honghuang Lin
A1 Badri N. Vardarajan
A1 Simon White
A1 Daniel Lancour
A1 Yiyi Ma
A1 Michael Schmidt
A1 Fangui Sun
A1 Mariusz Butkiewicz
A1 William S. Bush
A1 Brian W. Kunkle
A1 John Malamon
A1 Najaf Amin
A1 Seung Hoan Choi
A1 Kara L. Hamilton-Nelson
A1 Sven J. van der Lee
A1 Namrata Gupta
A1 Daniel C. Koboldt
A1 Mohamad Saad
A1 Bowen Wang
A1 Alejandro Q. Nato, Jr.
A1 Harkirat K. Sohi
A1 Amanda Kuzma
A1 Alzheimer’s Disease Sequencing Project (ADSP)
A1 Li-San Wang
A1 L. Adrienne Cupples
A1 Cornelia van Duijn
A1 Sudha Seshadri
A1 Gerard D. Schellenberg
A1 Eric Boerwinkle
A1 Joshua C. Bis
A1 Josée Dupuis
A1 William J Salerno
A1 Ellen M. Wijsman
A1 Eden R. Martin
A1 Anita L. DeStefano
YR 2018
UL http://biorxiv.org/content/early/2018/05/11/318857.abstract
AB The Alzheimer’s Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed “consensus calling,” to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.Abbreviations AD, Alzheimer’s disease; QC, Quality Control; LSSAC, Large-Scale Sequencing and Analysis Center; Broad, Broad Institute Genomics Service; Baylor, Baylor College of Medicine Human Genome Sequencing Center; WashU, Washington University-St. Louis McDonnell Genome Institute; WGS, whole genome sequencing; WES, whole exome sequencing; indel, insertion-deletion variants; VCF, variant control format; MI, Mendelian inconsistency; MC, Mendelian consistency; GWAS, genome-wide association study; VR, referent allele read depth; DP, overall read depth; MS, mapping score; GQ, genotype quality score; Ti/Tv, Transition/Transversion; CS, concordance code