Our study was motivated by the observations of ‘missing heritability’ in GWAS for complex human diseases (1–9). Several non-mutually exclusive explanations for the missing heritability have been proposed (1,4,7,8), including the hypothesis that disease susceptibility is genetically determined by a large number of common variants with small effects, which cannot be reliably identified using standard GWAS approaches. In the case of asthma, some measure of support for this hypothesis is provided by the observation that already in 2006 (prior to the first GWAS for asthma) variation in more than 100 genes was implicated in asthma susceptibility (33), yet many variants show only weak associations that have often proved difficult to replicate (34–36).
