correspondence nature genetics
Sir,
the era of modern allergy genetics started in 1997 with the Transatlantic Airway Conference at Key Biscayne, Florida. 20 years later, the paper of Ferreira et al. (1) marks the end of an era by reporting the largest study so far of asthma, „hay fever“ and atopic eczema in 180,000 cases. It is the result of an huge international effort of many named and unnamed scientists. Unfortunately, there are major impairments regarding scope of analysis, epidemiological and bioinformatics methods, interpretation and data release. Some issues even contradict nature genetics editorial policies (2), (3), (4).
Although the article title promises to show the shared genetic origin of asthma, hay fever (a lay term that should be avoided as misnomer) and atopic eczema, the answer remains elusive as only results of a pair-wise case-only association are given. For a shared genetic origin, the result of case-control associations for the possible intersections of the traits would need to be compared.
Having more individuals under study means of course that more regions will be discovered (5) than in earlier studies. Bigger, however, does not always mean better, if phenotypes are poorly defined. The online questionnaire of 23andme customers (6) has never been validated with clinical data although being used now in a multi-national, multi-ethnic and multi-language setting. Only a rudimentary baseline description has been released (7) while even results reported in this paper are not public available. More questions are being raised as UK Biobank is contributing most controls but US based 23andme most cases. One third of the studies used case ascertainment while the heterogeneity between studies is not discussed although the addition of 23andme samples does not only inflate but also removes association peaks (as an example see Supplement Figure 15, peak after region 83).
The interpretation of known or unknown region as presented in Figure 1 of the Ferreira et al. paper is misleading as several studies already contributed results to the GWAS catalogue that is used as a reference here. In some regions, the results are therefore just repetitions of earlier findings (Supplement Figure 57). The authors would also need to show for each of their new association that these are not just chance findings (Supplement Figure 2, region 13).
Unfortunately Ferreira is agnostic about 800 articles (8) including numerous high ranked articles from the pre-GWAS era (9-17). Many of these associations have been replicated more than 5 times (18). Even the strongest association in the online data supplement (Figure 36, region #14, IL1R1) has already been described in the pre-GWAS era (19). Why do the authors not even cite their own related work (20)? Why do they not mention another paper of the UK biobank that has nearly the same title (21)? Why do co-authors of the new paper publish in parallel an even larger study with another allergy protective SNP that is not reported here (22)?
The genes presented in table 1 are positional candidates being in the vicinity of a disease associated SNP. Just by eye-balling the partitioning of the region is not always optimal in particular where many sentinel SNPs had to be placed in one region. Regions are highly different with regard to gene content, SNP coverage, minor allele frequency and linkage disequilibrium (and therefore also the power to detect an association may vary). Unfortunately strong and robust associations are being treated equally along with only borderline significant associations when fed into a bioinformatics pipeline.
The outcome is somewhat trivial in the light of many experimental studies in the field. Producing a list of „druggable“ genes from some „sentinel“ SNPs is an in silico overprediction based on the assumed function of nearby genes. It misses the fact that there are real-life GWAS outcomes (23) that are already being tested in phase II studies like AMG 282, an IL33 antibody.
In conclusion, having now seen the largest study so far of allergy genetics, we are set back to the Transatlantic Airway Conference 1997 where the first positional candidate gene was announced by Slutsky and Zamel, reportedly a „scientific result without science“ (24).
References
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