Generalized Haplotype Transmission Probabilities in Nuclear Families with an Affected Sib Pair

• Activity Number: 310
• Type: Contributed
• Date/Time: Wednesday, August 11, 2004 : 8:30 AM to 10:20 AM
• Sponsor: Biometrics Section
• Author(s): Fang Xie*+ and Shelley Bull and Paul Corey
• Companies: Chiron Corporation and Samuel Lunenfeld Research Institute and University of Toronto
• Keywords: haplotype relative risks ; TDT ; linkage ; association ; sib pair

Abstract

TDT was first proposed to test for linkage in presence of an association by Spielman (1993). It was built on the early work of Falk and Rubinstein (1987) on the concept of haplotype relative risks (HRR). Assuming a single-locus model for the HRR under a recessive mode of inheritance, Ott (1989) showed how the test statistic depends on both the linkage and the association parameters for a biallelic marker. We generalize Ott's work to a general genetic model specified by penetrances and allele frequencies. We consider nuclear families with at least one parent who is heterozygous at a biallelic marker locus with one affect child. The joint distribution of transmitting and nontransmitting a particular marker allele from a heterozygous parent to his affected children is computed. The probability distribution of the TDT is verified to be a special case of this joint distribution. We further extend the model to include nuclear families with an affected sib pair, without the assumption of independent transmission from the parents to their children. A test with two degrees of freedom for linkage can be constructed using the joint haplotype distribution for this type of nuclear families.