A first trial of retrospective collaboration for positional cloning in complex inheritance: Assay of the cytokine region on chromosome 5 by the Consortium on Asthma Genetics (COAG)

The central problem of complex inheritance is to map oligogenes for disease susceptibility, integrating linkage and association over samples that diff er in several ways. Combination of evidence over multiple samples with 1,03 7 families supports loci contributing to asthma susceptibility in the cytok ine region on 5q [maximum logarithm of odds (lod) = 2.61 near IL-4], but no evidence for atopy. The principal problems with retrospective collaboratio n on linkage appear to have been solved, providing far more information tha n a single study. A multipoint lod table evaluated at commonly agreed refer ence loci is required for both collaboration and metaanalysis, but variatio ns in ascertainment, pedigree structure, phenotype definition, and marker s election are tolerated. These methods are invariant with statistical method s that increase the power of lods and are applicable to all diseases, motiv ating collaboration rather than competition. In contrast to linkage, positi onal cloning by allelic association has yet to be extended to multiple samp les, a prerequisite for efficient combination with linkage and the greatest current challenge to genetic epidemiology.