Findings in genome‐wide association studies on asthma lack generalisation

To clarify the challenges for asthma genetics studies in the era of genome-wide association studies (GWASs), we recently reviewed (1) the published GWASs on asthma and its related phenotypes. We anticipated that because of the multifactorial, polygenic, modes of inheritance of asthma, the findings of the initial GWASs would rarely be replicated. Recently, two more GWASs on asthma were published, and consistent with our view, they described the difficulties in generalising the findings from GWASs on asthma (2, 3). A recently published study in the Journal of Allergy and Clinical Immunology (3) investigated African-ancestry populations for asthma using Illumina BeadChips and localised three single nucleotide polymorphisms (SNPs), respectively, mapping to the alpha-1B-adrenergic receptor gene, the prion-related protein gene and the dipeptidyl peptidase 10. However, replication tests by the authors showed that these findings could not be generalised to a European population, nor to four African American populations. The authors also attempted to replicate in their populations of African ancestry the initial asthma GWAS finding of ORMDL3 as an asthma candidate gene in a European population (4). In the African populations, they found no convincing evidence for association with any genotyped SNPs in the ORMDL3 gene and its flanking regions. Mathias et al. concluded that identifying true associations for a heterogeneous disease, such as asthma, is complex, particularly in African populations with more genetic variations relative to other ethnic groups (3). Another GWAS implicated a chromosome region (9q21.31) harbouring SNPs, mapping to Transducin-like enhancer protein 4 gene (TLE4), related to the susceptibility to asthma in Mexican children (2). Because of the relatively small sample size and insufficient power, this GWAS did not identify any SNPs that met genome-wide significance. The 11 most significantly associated SNPs identified in the initial analysis were selected to test the replication in an additional Mexican population. Using Bonferroni correction for multi-comparisons of the 11 SNPs, they did not find any significant associations with asthma in the replication population. They also attempted to confirm the TLE4 findings in other GWA populations (4–6) and failed to find convincing replications. In order to evaluate 246 previously implicated asthma candidate genes with childhood asthma in the Mexican population, the same author group re-analysed the GWA data and only replicated four genes (TGFB1, IL1RL1, IL18R1, and DPP10) that might contribute to childhood asthma susceptibility in the Mexican population (7). This further indicated the feature of findings in asthma genetics: lack of generalisation. Three commonly used genetic investigation strategies have been extensively utilised for asthma genetic research, namely candidate gene association study, linkage study following position cloning and newly evolved GWA studies. More than 100 genes have been suggested to be associated with asthma-like phenotypes. However, no genotype contributes more than a few percent to the risk for developing asthma (1), and no asthma-related genotype has been found to be associated with asthma in all populations tested (8). Furthermore, several SNPs have opposite alleles as risk factors for asthma in different situations or populations (9, 10). We compared the genetic profiles for several commonly reported asthma candidate genes in populations with and without Western lifestyle and experiencing significant disparities in terms of prevalences of asthma and allergy. Our studies found that the different genetic profiles were dominant in different populations, dependent on their domiciliary environments (10, 11). It is generally agreed that multiple genes with modest effects are likely to operate through interactions with multiple environmental factors in asthma development. With the advent of new genotyping technologies, it is also expected that GWA studies will identify several asthma candidate genes. However, the initial GWA studies on asthma confirm the complexity of identifying true associations in asthma genetic studies and that asthma genetic research is still in its infancy. crj_213 8.9