Table 2. Studies with a hypothesis-free approach.

Definition of exacerbation	Gene	Associated variants	Reference Number
Hospitalization	CDHR3	rs6967330	23
# Investigators performed a GWAS of a specific asthma phenotype characterized by recurrent and severe exacerbations occurring between 2 and 6 years of age in Denmark. They identified five loci with genome-wide significant associations. The 4 genes GSDMB, IL33, RAD50, and IL1RL1, were previously reported as asth- ma susceptibility loci but CDHR3 was a new susceptibility gene.
OSB	CTNNA3, SEMA3D	rs1099729, rs99331	24
# A GWAS focusing less severe AEs identified several variants in CTNNA3 and SEMA3D as risk loci in two independent childhood asthma clinical trials in the US. Among them, rs10997296 in CTNNA3 locus with a genome-wide significance was associated with CTNNA3 mRNA expression in CD4+ cells from asthmatic pa- tients and rs993312 in SEMA3D locus replicated in a clinical biobank database of childhood and young adult asthmatics, although its significance did not reach a genome-wide significance in the primary analysis
ER visit or hospitalization	NA	160 SNPs	28
# Investigators performed a GWAS of severe AEs in a childhood asthma clinical trial in the US and identified a list of top GWAS SNPs based on Random Forest im- portance score. With only 417 childhood asthmatics, using 160 SNPs, age, sex, pre-bronchodilator FEV1 predicted percentage, and treatment group, they could generate a good predictive model for severe AEs, with a >0.66 area under the curve and about 0.66 sensitivity and 0.6 specificity

AE, Asthma exacerbation; ER, Emergency room; FEV1, Forced expiratory volume in 1 second; NA, Not applicable; OSB, Oral steroid burst; SNP, Single nucleotide polymorphism.