LAUSR

Introduction: Genome-wide association studies (GWAS) have discovered >30 loci associated with asthma risk. Despite the characterization of asthma as a heterogeneous disorder, most GWAS evaluate asthmatics as a single population. To explore whether genetics are associated with this phenotypic heterogeneity, we whole-genome sequenced (WGS) >5,000 severe, uncontrolled asthmatics who were clinically well characterized. Methods: After quality-control we had WGS data for 3,223 asthmatics of European ancestry. We performed common (minor allele frequency, MAF, ≥1%) variant and rare (MAF Results: Our risk analysis replicated ten previously reported asthma risk loci and identified a novel SNP in THSD4 that was significantly associated with asthma risk (P=4.43x10-8). This locus has been previously associated with both COPD risk and FEV1. In the rare variant burden GWAS, loss-of-function variants in IL33 were associated with decreased risk. We observed no overlap among the top genetic association signals for asthma risk and the other phenotypes. However, we found significant enrichment of genes implicated in Primary Ciliary Dyskinesia, PCD, as well as motile cilia genes, associated with asthma risk in the low-eosinophil asthmatics (P Conclusions: We found a new genome-wide significant association with asthma risk at a SNP in THSD4. We also identified enrichment of PCD genes with asthma risk among eosinophil-low patients. Replication of these findings in an independent cohort is needed to confirm sharing of asthma risk factors with COPD and PCD.