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

Adam C. Naj*, Honghuang Lin, Badri N. Vardarajan, Simon White, Daniel Lancour, Yiyi Ma, Michael Schmidt, Fangui Sun, Mariusz Butkiewicz, William S. Bush, Brian W. Kunkle, John Malamon, Najaf Amin, Seung Hoan Choi, Kara L. Hamilton-Nelson, Sven J. van der Lee, Namrata Gupta, Daniel C. Koboldt, Mohamad Saad, Bowen WangAlejandro Q. Nato, Harkirat K. Sohi, Amanda Kuzma, Li San Wang, L. Adrienne Cupples, Cornelia van Duijn, Sudha Seshadri, Gerard D. Schellenberg, Eric Boerwinkle, Joshua C. Bis, Josée Dupuis, William J. Salerno, Ellen M. Wijsman, Eden R. Martin, Anita L. DeStefano, Alzheimer's Disease Sequencing Project (ADSP)

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)808-818
Number of pages11
Issue number4
Publication statusPublished - 1 Jul 2019

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