Family-based tests for associating haplotypes with general phenotype data: Application to asthma genetics

Authors

  • Steve Horvath,

    Corresponding author
    1. Departments of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California
    2. Department of Biostatistics, School of Public Health, UCLA, Los Angeles, California
    • Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, UCLA, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088
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  • Xin Xu,

    1. Program for Population Genetics, Harvard School of Public Health, Boston, Massachusetts
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  • Stephen L. Lake,

    1. Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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  • Edwin K. Silverman,

    1. Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
    2. Division of Pulmonary and Critical Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
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  • Scott T. Weiss,

    1. Program for Population Genetics, Harvard School of Public Health, Boston, Massachusetts
    2. Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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  • Nan M. Laird

    1. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
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Abstract

We provide a general purpose family-based testing strategy for associating disease phenotypes with haplotypes when phase may be ambiguous and parental genotype data may be missing. These tests for linkage and association can be used in candidate gene studies with tightly linked markers. Our proposed weighted conditional approach extends the method described in Rabinowitz and Laird [Human Heredity 504:227–233, 2000] to multiple markers. It is attractive because it provides haplotype tests for family-based studies that are efficient and robust to population admixture, phenotype distribution specification, and ascertainment based on phenotypes. It can handle missing parental genotypes and/or missing phase in both offspring and parents. It yields either haplotype-specific (univariate) tests or multi-haplotype (global) tests. This extension has been implemented in the freely available software haplotype FBAT. We used the haplotype FBAT program to test for associations between asthma phenotypes and single nucleotide polymorphisms (SNPs) in the beta-2 adrenergic receptor gene. Whereas no single SNP showed significant association with asthma diagnosis or bronchodilator responsiveness (quantitative trait), a haplotype-based global test found a highly significant association with asthma diagnosis (P value <0.00005) and the measure of bronchodilator responsiveness (P value =0.016). Genet Epidemiol 26:61–69, 2004. © 2003 Wiley-Liss, Inc.

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