Polygenic effects of four asthma loci on chromosome 17 were associated with prevalence of recurrent wheeze and asthma during childhood
GRS analysis determined that the combined, weighted effects of 4 reported asthma variants (rs3816470, rs3902920, rs8076131, rs12603332) on chromosome 17q12-21 had the strongest association with recurrent wheeze between ages 2-5 in the CHILD cohort (SupplementalData 4 ). This association using a regression model was significant for the full, multi-ethnic cohort (p = 1.5e-08) and the Caucasian sub-cohort (p = 8.9e-05; Supplemental Figure S6 ). The SNV rs3816470 was associated with reduced risk (i.e. protective effect) whereas variants rs3902920, rs8076131, rs12603332 were associated with increased risk of recurrent wheeze. Three of these variants (rs3816470, rs8076131, and rs12603332) are known eQTLs correlated with the expression of nearby genes ORMDL3 andGSDMB within lung and immune cells, reported by the Genotype-Tissue Expression (GTEx) project.
In a separate GRS analysis targeting asthma diagnosis by age 5 in the CHILD Study, the most correlated GRS (p=9.4e-08) consisted of the same four variants as for recurrent wheeze described above.Supplemental Figure S7 demonstrates that GRS including additional variants is less associated with asthma and recurrent wheeze (shown in p-value).
The prevalence of recurrent wheeze was 8.7% among children in the low GRS group, 14.7% in moderate GRS group and 19.7% in high GRS group (Figure 3a ). This shows a 2.3-fold increase in wheeze prevalence between the low vs. high GRS groups. Similarly, the prevalence of asthma in the low GRS group was 9.3%, 15.5% in the moderate GRS group and 19.9% in the high GRS group (Figure 3b ). This indicates a 2.2-fold increase in asthma prevalence between the low and high GRS groups.