Inheritance Model Introduces Differential Bias in CNV Calls Between Parents and Offspring

Authors

  • Sulgi Kim,

    1. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle,, Washington
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  • Steven P. Millard,

    1. Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
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  • Chang-En Yu,

    1. Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
    2. Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington
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  • Lesley Leong,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
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  • Allen Radant,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
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  • Dorcas Dobie,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
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  • Debby W. Tsuang,

    1. Mental Illness Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
    2. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
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  • Ellen M. Wijsman

    Corresponding author
    1. Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington
    2. Department of Genome Sciences, School of Medicine, University of Washington, Seattle, Washington
    • Division of Medical Genetics, Department of Medicine, University of Washington, Seattle,, Washington
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Correspondence to: Ellen M. Wijsman, Division of Medical Genetics, School of Medicine, University of Washington, BOX 357720, Seattle, WA 98195-7720. E-mail: wijsman@u.washington.edu

Abstract

Copy Number Variation (CNV) is increasingly implicated in disease pathogenesis. CNVs are often identified by statistical models applied to data from single nucleotide polymorphism panels. Family information for samples provides additional information for CNV inference. Two modes of PennCNV (the Joint-call and Posterior-call), which are some of the most well-developed family-based CNV calling methods, use a “Joint-model” as a main component. This models all family members’ CNV states together with Mendelian inheritance. Methods based on the Joint-model are used to infer CNV calls of cases and controls in a pedigree, which may be compared to each other to test an association. Although benefits from the Joint-model have been shown elsewhere, equality of call rates in parents and offspring has not been evaluated previously. This can affect downstream analyses in studies that compare CNV rates in cases vs. controls in pedigrees. In this paper, we show that the Joint-model can introduce different CNV call rates among family members in the absence of a true difference. We show that the Joint-model may analytically introduce differential CNV calls because of asymmetry of the model. We demonstrate these differential call rates using single-marker simulations. We show that call rates using the two modes of PennCNV also differ between parents and offspring in one multimarker simulated dataset and two real datasets. Our results advise need for caution in use of the Joint-model calls in CNV association studies with family-based datasets. Genet. Epidemiol. 36:488-498, 2012. © 2012 Wiley Periodicals, Inc.

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