Linkage analysis of a cluster-based quantitative phenotype constructed from pulmonary function test data in 27 multigenerational families with multiple asthmatic members

Objective: To identify genes involved in phenotypes that increase one's risk for developing asthma, a complex disease that is likely genetically heterogeneous. Unlike other approaches to locus discovery in the presence of heterogeneity, this method seeks loci that segregate in all or most ascertained families while recognizing that other genes and environmental factors that modify the action of the common gene may vary across families. Methods: The method is based on seeking groups of families that differ, between groups, in the way affected idndividuals express the genotype. Then we use the distance of each individual to the cluster center for his family to define a quantitative trait. This quantitative trait is then subjected to a genome scan using variance components methods. Results: The method is applied to a data set of 27 multigenerational families with asthma, and a novel locus at 2q33 (at 210 cM) is identified. Conclusions: The proposed method has the potential to identify loci near genes that increase risk for asthma related phenotypes. The method could be used for other complex disorders that exhibit locus heterogeneity.