Multipoint Linkage Analysis of the Pseudoautosomal Regions, Using Affected Sibling Pairs

Abstract

Affected sibling pairs are often the design of choice in linkage-analysis studies with the goal of identifying the genes that increase susceptibility to complex diseases. Methods for multipoint analysis based on sibling amount of sharing that is identical by descent are widely available, for both autosomal and X-linked markers. Such methods have the advantage of making few assumptions about the mode of inheritance of the disease. However, with this approach, data from the pseudoautosomal regions on the X chromosome pose special challenges. Same-sex sibling pairs will share, in that region of the genome, more genetic material identical by descent, with and without the presence of a disease-susceptibility gene. This increased sharing will be more pronounced for markers closely linked to the sex-specific region. For the same reason, opposite-sex sibling pairs will share fewer alleles identical by descent. Failure to take this inequality in sharing into account may result in a false declaration of linkage if the study sample contains an excess of sex-concordant pairs, or a linkage may be missed when an excess of sex-discordant pairs is present. We propose a method to take into account this expected increase/decrease in sharing when markers in the pseudoautosomal region are analyzed. For quantitative traits, we demonstrate, using the Haseman-Elston method, (1) the same inflation in type I error, in the absence of an appropriate correction, and (2) the inadequacy of permutation tests to estimate levels of significance when all phenotypic values are permuted, irrespective of gender. The proposed method is illustrated with a genome screen on 350 sibling pairs affected with type I diabetes.

A Novel Framework for Sib Pair Linkage Analysis

“…Data for pseudoautosomal regions could be analyzed with this approach; however, care should be taken in interpretation. The fact that same-sex pairs will generally show increased sharing in these regions can elicit misleading results if such sharing inequalities are not accounted for (Dupuis and Van Eerdewegh 2000). Finally, although quantitative traits can be considered with this approach, they must be dichotomized and, therefore, are not used directly.…”

X-Linked Extension of the Revised Haseman-Elston Algorithm for Linkage Analysis in Sib Pairs

“…Therefore, we intend extending this work to the case of selected samples similar to the work done for autosomal loci, such as selecting individuals from the tails of a distribution [Carey and Williamson, 1991], or extreme discordant sib pairs Zhang, 1995, 1996], which can be expected to increase the power to detect linkage to the X chromosome. Multipoint versions of X linkage and linkage to pseudoautosomal regions [Dupuis and van Eerdewegh, 2000] using sib pairs in the context of the H-E method will be the focus of future research. The X-linked extension discussed above and its multipoint version will be implemented in the computer program SIBPAL [S.A.G.E., 2002].…”

Non‐Parametric Linkage

“…Cordell et al, 1995a) and are implemented in most analysis software. Particular care must be taken for pseudoautosomal data (Dupuis and Van Eerdewegh, 2000).…”