LAUSR

Asthma is a polygenic heterogeneous condition with phenotypic variation through the life course. Using 5 wheezing phenotypes from birth to adolescence identified in more than 7,000 children in the Avon Longitudinal Study of Parents and Children (ALSPAC) [JACI 2016], a de-novo GWAS study was conducted to identify new genetic markers of individual wheezing phenotypes. Trinculo software [Bioinformatics, 2016] was used to perform power test calculations of simulated GWAs data and to conduct a GWAS of a 5-category wheezing phenotype on 1000 genome data available in ALSPAC. Regional plots were examined for GWAS-significant and secondary signals (p-value −5 ). Power calculations with a simulated 5-category phenotype showed ≥79% power to detect exclusive associations (multinomial Odds Ratio≥1.40) in common risk alleles (Risk Allele Frequency (RAF)≥0.25) for a sub-phenotype with at least 1182 cases (≥67% power for RAF≥0.45 and 860 cases). Chromosome 17q21.1 region was confirmed as the main GWAS-significant hit for early onset wheezing that persists to age 6-7 years or till adolescence. A potential set of exclusive markers of early onset wheeze that remits by age 11 years was identified for the first time in this study, including regions 4p15.31 (near KCNIP4 gene) and 6p22.1 (near HLA-G gene) previously associated with asthma-related phenotypes. These results point towards genetic heterogeneity of the wheezing phenotypes. Replication and further research is needed to disentangle the endotypes that underpin specific wheezing phenotypes and how to translate this knowledge for clinical benefit.