Powerful designs for genetic association studies that consider twins and sibling pairs with discordant genotypes

Authors

  • Jennifer Wessel,

    1. Center for Human Genetics and Genomics, University of California, San Diego, La Jolla, California
    2. Department of Psychiatry, University of California, San Diego, La Jolla, California
    3. Department of Family and Preventive Medicine, Division of Epidemiology, University of California, San Diego, La Jolla, California
    4. Graduate School of Public Health, San Diego State University, San Diego, California
    5. Scripps Genomic Medicine, The Scripps Research Institute, La Jolla, California
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  • Andrew J. Schork,

    1. Department of Psychiatry, University of California, San Diego, La Jolla, California
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  • Hemant K. Tiwari,

    1. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama
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  • Nicholas J. Schork

    Corresponding author
    1. Center for Human Genetics and Genomics, University of California, San Diego, La Jolla, California
    2. Department of Psychiatry, University of California, San Diego, La Jolla, California
    3. Department of Family and Preventive Medicine, Division of Biostatistics, University of California, San Diego, La Jolla, California
    4. Scripps Genomic Medicine, The Scripps Research Institute, La Jolla, California
    • Scripps Genomic Medicine, Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-275A, 10550 North Torrey Pines Road, La Jolla, CA 92037
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Abstract

Genetic association studies are becoming commonplace due to the availability of cost-effective yet sophisticated DNA sequencing and genotyping resources and technologies. In addition, technologies designed to identify molecular and subclinical phenotypes that reflect disease pathogenesis are continually being developed and refined (consider, e.g., imaging technologies, microarray-based gene expression and proteomic platforms, histological analyses of excised tissues, etc.). Unfortunately, the large-scale use of many of these molecular and subclinical phenotyping technologies in genetic association studies is difficult logistically and is currently cost-prohibitive. In this paper, we consider efficient designs for testing the association between particular genetic variations and expensive, yet appropriate, subclinical phenotypes of relevance to a disease that take advantage of twins or sibling pairs discordant for genotypes at the locus (or loci) being tested. We demonstrate that including genotypically discordant twins or siblings in an association study can result in a substantial increase in power over designs that use monozygotic twins or only unrelated individuals. We ultimately argue that, from a practical standpoint, sampling from existing family or twin-based cohorts in which: (1) follow-up studies of a genetic association are warranted in order to assess the in vivo significance of an association with respect to more refined pathological phenotypes; and/or (2) large-scale, genome-wide linkage and association studies have been pursued that have focused on clinical endpoints for which the study subjects have consented to more elaborate follow-up studies, is a powerful way to test associations. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc.

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