Meta-analysis for linkage to asthma and atopy in the chromosome 5q31-33 candidate region

Asthma is a common, complex human disease. Gene discovery in asthma has bee n complicated by substantial etiological heterogeneity, the possibility of genes of small effect and the concomitant requirement for large sample size s. Linkage to asthma phenotypes has been investigated most intensively in t he 5q chromosomal region, although results have been inconsistent across st udies and all studies have had modest sample sizes. One potential solution to these issues is to combine data from multiple studies in a retrospective metaanalysis by pooling either summary statistics or raw data. The Interna tional Consortium on Asthma Genetics combined data from 11 data sets (n = 6 277 subjects) to investigate evidence for linkage of 35 markers spanning th e cytokine cluster on chromosome 5q31-33 to 'asthma' dichotomy and total se rum immunoglobulin E (IgE) levels. Chromosome 5q markers typed in different centers were integrated into a consensus map to facilitate effective data pooling. Multipoint linkage analyses using a new Haseman-Elston method were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by meta-analytic methods. Our results did not provide any evidence significant at the 5% level that loci conferri ng susceptibility to asthma or atopy are present in the 5q31-33 region; how ever, there was some weak evidence (empirical P = 0.077) of linkage to asth ma affection. This study suggests that loci in 5q31-33 have at most a modes t effect on susceptibility to asthma or total serum IgE levels, may not be detectable or present in all human populations and are difficult to detect even using combined linkage evidence from 2400-2600 full sibling pairs.