A multiple splitting approach to linkage analysis in large pedigrees identifies a linkage to asthma on chromosome 12

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Abstract
Large genealogies are potentially very informative for linkage analysis. However, the software available for exact non‐parametric multipoint linkage analysis is limited with respect to the complexity of the families it can handle. A solution is to split the large pedigrees into sub‐families meeting complexity constraints. Different methods have been proposed to “best” split large genealogies. Here, we propose a new procedure in which linkage is performed on several carefully chosen sub‐pedigree sets from the genealogy instead of using just a single sub‐pedigree set. Our multiple splitting procedure capitalizes on the sensitivity of linkage results to family structure and has been designed to control computational feasibility and global type I error. We describe and apply this procedure to the extreme case of the highly complex Hutterite pedigree and use it to perform a genome‐wide linkage analysis on asthma. The detection of a genome‐wide significant linkage for asthma on chromosome 12q21 illustrates the potential of this multiple splitting approach. Genet. Epidemiol. 2009.