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Genomics. 2018 May 29. pii: S0888-7543(18)30281-7. doi: 10.1016/j.ygeno.2018.05.004. [Epub ahead of print]

Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project.

Author information

1
Department of Biostatistics and Epidemiology, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: adamnaj@pennmedicine.upenn.edu.
2
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
3
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
5
Department of Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.
6
John P. Hussman Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
7
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
8
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
9
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
10
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
11
Medical and Population Genetics Program, Broad Institute, Cambridge, MA, USA.
12
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
13
Department of Biostatistics, USA; Division of Medical Genetics, USA.
14
Department of Statistics, University of Washington, Seattle, WA, USA.
15
Division of Medical Genetics, USA.
16
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; The Framingham Heart Study, Framingham, MA, USA.
17
The Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
18
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Human Genetics Center University of Texas Health Science Center, Baylor College of Medicine, Houston, TX, USA.
19
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
20
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; The Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Abstract

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.

KEYWORDS:

Atlas; Consensus calling; GATK; Mendelian inconsistencies; Quality control; Whole genome sequencing

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