Mixed modeling and multiple imputation for unobservable genotype clusters

Authors

  • A. S. Foulkes,

    Corresponding author
    1. Division of Biostatistics, University of MA School of Public Health and Health Sciences, 715 N. Pleasant Street, Amherst, MA 01003-9304, U.S.A.
    • Division of Biostatistics, University of MA School of Public Health and Health Sciences, 715 N. Pleasant Street, Amherst, MA 01003-9304, U.S.A.
    Search for more papers by this author
  • R. Yucel,

    1. Division of Biostatistics, University of MA School of Public Health and Health Sciences, 715 N. Pleasant Street, Amherst, MA 01003-9304, U.S.A.
    Search for more papers by this author
  • M. P. Reilly

    1. Cardiovascular Institute, University of Pennsylvania School of Medicine, 421 Curie Blvd, Philadelphia, PA 19104, U.S.A.
    Search for more papers by this author

Abstract

Understanding the genetic contributions to complex diseases will require consideration of interaction across multiple genes and environmental factors. At the same time, capturing information on allelic phase, that is, whether alleles within a gene are in cis (on the same chromosome) or in trans (on different chromosomes), is critical when using haplotypic approaches in disease association studies. This paper proposes a combination of mixed modeling and multiple imputation for assessing high-order genotype–phenotype associations while accounting for the uncertainty in phase inherent in population-based association studies. This method provides a flexible statistical framework for controlling for potential confounders and assessing gene–environment and gene–gene interactions in studies of unrelated individuals where the haplotypic phase is generally unobservable. The proposed method is applied to a cohort of 626 subjects with human immunodeficiency virus (HIV) to assess the potential contribution of four genes, apolipoprotein-C-III, apolipoprotein-E, endothelial lipase and hepatic lipase in predicting lipid abnormalities. A simulation study is also presented to describe the method performance. Copyright © 2007 John Wiley & Sons, Ltd.

Ancillary