Allele-Sharing Linkage Analysis on Subsets of Families Stratified Based on an Associated Allele

• Activity Number: 335
• Type: Contributed
• Date/Time: Wednesday, August 6, 2003 : 8:30 AM to 10:20 AM
• Sponsor: Biometrics Section
• Author(s): Chun Li*+ and Laura Scott and Michael Lee Boehnke
• Companies: Vanderbilt University and University of Michigan and University of Michigan, Ann Arbor
• Keywords: association ; linkage ; allele sharing ; gene mapping

Abstract

To fine-map genes we often test for disease-marker association in chromosomal regions with evidence for linkage. Given a marker allele associated with disease, we ask if this allele, or one in LD with it, could account in part for the observed linkage signal. We address this question by determining if families selected based on presence of an associated allele show stronger evidence of linkage as measured by increased allele-sharing IBD. Some common strategies for selecting families are biased for or against linkage in the marker region. For affected sibship data, we describe three unbiased weighted subsetting schemes, corresponding to dominant, recessive, and additive models. To determine if linkage signal can be partly attributed to the presence of the associated allele, we introduce procedures to test for association of a genotype-based family weight variable with excess allele IBD sharing. For 500 ASPs, the tests are powerful to detect such an association, even for disease models with sib relative risk as low as 1.1, or when there is no evidence for linkage due to sampling variation. The latter property makes our method a new tool for detecting linkage as well as association.