Approaches to genetic studies of asthma.

It is important to remember that any postulated linkage needs to be confirmed and the identification of one major locus does not mean that other major loci are not also present. The failure to replicate a postulated linkage has become a serious problem in studies on the genetics of complex disorders. A major reason for failure to replicate, as discussed by Risch (30) may be the interpretation of a LOD score calculated under an unlikely model. Analysis of a LOD score assumes that the underlying genetic model for the disorder being studied is known. Clear evidence for a specific genetic model for asthma has yet to be delineated. There are several obvious reasons for failure to confirm a postulated linkage. For purposes of replication, it is important to use the same definition of the affected phenotype and the same genetic model that were used in the original study. The presence of genetic heterogeneity is often given as a possible reason for failure to replicate. It seems unlikely that this should be a reason for failure to replicate across relatively homogeneous populations (such as Caucasian families from the U.S.A. and England). However, heterogeneity may be confounded with differing expression of genes because of exposures to different allergens. In addition, if there are several genes that interact in disease expression (oligogenic inheritance), it may be very difficult to replicate a true linkage (31). In different sets of families, different proportions of the genes involved may be present and the linked gene may not be detected in all studies.(ABSTRACT TRUNCATED AT 250 WORDS)