Age-Of-Onset Genome-Wide Association Studies In Allergic Disease

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Susceptibility to allergic diseases can be predicted by genome-wide association studies (GWAS) based on biobanks of sequenced DNA from people with said diseases. Knowing the likely age-of-onset of these diseases would be helpful for risk management and lifestyle adjustment. Likely age-of-onset is not knowable from allergic disease risk alone, although they are related. Separate GWAS for age-of-onset must be performed, however to date such approaches have been limited.

Gerard H. Koppelman of University Medical Center Groningen, The Netherlands, and colleagues, aimed to identify novel genetic loci for age-of-onset, as a whole, for the group of asthma, hay fever and eczema allergies. This was achieved by GWAS and the relationship between age-of-onset and disease risk was tested. The results were published in the journal PLoS Genetics.

The UK biobank was the source of the information, where the mean onset of the aforementioned allergic diseases was 26 years and the median was 22 years. Following analysis, 50 variants in 40 loci were determined to be associated with age-of-onset in a statistically independent manner. Of these 50 variants, 44 have not been implicated in the age-of-onset of any allergic disease at the genome-wide significance level previously.

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It was found, as hypothesized, that age-of-onset variants also predict allergic disease risk; 48 of the 50 sentinel variants were significantly associated with disease risk by GWAS. This may suggest allergic disease etiology similar to cancer, in that a certain sequence of events must be fulfilled before disease initiation, which may be stochastic, or time dependent, and therefore the greater burden of pre-existing fulfilled “steps” the earlier allergic disease emerges in those individuals.

The study may be limited by recall bias, as the age-of-onset was self-reported and the youngest participant was 38 years, whereas the oldest was 70 years at the time of the study. Comparison of the reported age-of-onset between two surveys performed up to 7 years apart, in the same individuals, suggest that this may not be a serious problem, however older participants tended to recall less reliably.

“In conclusion, we show that novel risk loci for allergic disease can be identified by extending the analytical approach that we reported recently to the analysis of age-of-onset of asthma, hay fever and eczema. GWAS of other complex diseases might also benefit from considering age-of-onset information. We found 76 specific genetic associations with allergic disease, of which 28 had not previously been reported. We implicate 81 genes as likely targets of the associated variants and provide further evidence that individuals with early disease onset have a greater burden of genetic risk factors for allergic disease than individuals with late disease onset,” stated the authors.