GWAS of recurrent wheeze and asthma validated associations with known asthma loci
GWAS of recurrent wheeze identified 98 significantly associated SNVs (p < 5e-8) in the full (multi-ethnic) cohort (n=2835,Figure 1a ). No significant findings were identified in the smaller, Caucasian sub-cohort (n=2090, Supplemental Figure S4 ). All of the associated variants are located on chromosome 17q12 - 17q21, are in strong LD (r2>0.8), and maps to known genesGRB7 , IKZF3 , ZPBP2 , GSDMB , and ORMDL3(Figure 1b ). Annotation analysis identified that 5% of these variants are coding or regulatory (3% missense, 1% splice acceptor, and 1% located within known regulatory regions) whereas the majority are non-coding (53% intronic, 19% downstream, 13% intergenic, 4% located within the 5’ or 3’-untranslated regions (UTRs), 2% are synonymous; Supplemental Figure S5) . Moreover, 28 SNVs are cis-eQTLs identified from lymphoblastoid cell lines, which were correlated with the expression of nearby genes. Annotations of the identified variants using Ensemble Variant Effect Predictor database show association with traits such as allergy, atopic march, hay fever and eczema.(33) Additional annotation details of associated SNVs can be found in Supplemental Data 2 .
GWAS of physician diagnosed asthma in both the multi-ethnic, full cohort (Figure 2a ) and the Caucasian sub-cohort (Figure 2b ) identified one significant association for variant rs145454327. This SNV is located within an intronic region of the Calmodulin-regulated spectrin-associated protein 2 (CAMSAP2) gene on chromosome 1. Chromatin state model analysis of fetal lung tissue using RegulomeDB identified that this variant is located within an enhancer region (chr1:200753800..200754400), and affects the motif for 4 transcription factors: GATA-4, TBP, FOXP1, and Sox8 (Supplemental Data 3 ).