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)

Abstract

The central problem of complex inheritance is to map oligogenes for disease susceptibility, integrating linkage and association over samples that differ in several ways. Combination of evidence over multiple samples with 1,037 families supports loci contributing to asthma susceptibility in the cytokine region on 5q [maximum logarithm of odds (lod) ‫؍‬ 2.61 near IL-4], but no evidence for atopy. The principal problems with retrospective collaboration on linkage appear to have been solved, providing far more information than a single study. A multipoint lod table evaluated at commonly agreed reference loci is required for both collaboration and metaanalysis, but variations in ascertainment, pedigree structure, phenotype definition, and marker selection are tolerated. These methods are invariant with statistical methods that increase the power of lods and are applicable to all diseases, motivating collaboration rather than competition. In contrast to linkage, positional cloning by allelic association has yet to be extended to multiple samples, a prerequisite for efficient combination with linkage and the greatest current challenge to genetic epidemiology. T he central problem of complex inheritance is to map oligogenes for disease susceptibility. Even the largest study has low power to map genes of small effect by the complementary methods of linkage and allelic association, and a confirmatory sample is necessary even for genes of large effect. Often the significance of multiple samples is controversial. These considerations favor combination of evidence, for which there are three approaches called meta-analysis, prospective collaboration, and retrospective collaboration.Meta-analysis typically uses published summaries and so is comprehensive. It would be the method of choice if publication did not favor positive results and the data were summarized in a way that distinguishes information, effect, and location, like lod scores for major loci. Unfortunately, studies of complex inheritance differ widely in phenotype definition, selection of families or cases and controls, choice of marker loci, and statistical analysis. The only common denominator is a nominal significance level, which is usually not specified unless it lies beyond an arbitrary threshold. Such material, although peer-reviewed, is subject to many errors and biases but can be used to define candidate regions (1).Prospective collaboration is typified by national consortia like the Collaborative Study on the Genetics of Asthma (2). Each member of the consortium tries to follow the same protocol, including phenotype definitions, sampling scheme, and markers. This effort assures uniformity but makes no use of the many studies with different but equally defensible protocols.Retrospective collaboration is typified by the international Consortium on Asthma Genetics (COAG). Each member of the consortium provides data published independently with no agreement about protocol. The analysis must be coherent, or else would be no more than a meta-analysis of a subse...

Linkage analysis of the 5q31–33 candidate region for asthma in 240 UK families

“…The initial focus of COAG will be to undertake a combined analysis of linkage data from several studies including this one on chromosome 5q31-33. 29 In conclusion the results of this study support the hypothesis that the 5q31-33 region is linked to susceptibility to asthma, however there was no apparent linkage of measures of atopy in this population. Further typing of both STS markers and polymorphisms in candidate genes within this region will be needed to further understand this linkage and how it relates to both the atopy and asthma phenotypes.…”

A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

“…The study showed suggestive linkage for asthma (LOD = 2.6) but no evidence for atopy [8]. Although it is not known whether human genes in the 5q31 cytokine cluster are genetic regulators for atopic disorders, experimental models of asthma have shown the importance of both IL4 and IL13 signaling.…”

Interleukin-12B Gene Polymorphism does not Confer Susceptibility to Graves' Ophthalmopathy in Japanese Population

“…This might suggest that these loci are specific to East Asian populations. The loci in regions 5q31-q33 have also been identified as being susceptible to IgE synthesis [17,18]. This region encodes a cluster of cytokine genes, including IL-3, IL-4, IL-5, IL-9, IL-12B and IL-13, which are involved in inflammation in both thyroid and orbit, and IgE synthesis [19].…”