Abstract
The coexistence of asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP) is associated with allergic phenotypes, disease severity and failure of first-line treatment for both asthma and CRSwNP. Recent studies have highlighted shared genetic components for these diseases. To better understand this shared component, we perform genome-wide meta-analyses of asthma (n = 71,481), CRSwNP (n = 9626) and chronic rhinosinusitis without nasal polyposis (CRSsNP, n = 15,448) in FinnGen and UKB (685,602 controls). We detect 131 genomic associations, including 17 novel loci for asthma, 33 novel loci for CRSwNP, and one for CRSsNP. A shared impact on asthma and CRSwNP is observed at 71 loci. A cross-trait meta-analysis using all disorders further implicates 17 loci associated with asthma or asthma and CRSwNP. We also find 17 nonsynonymous associating variants, including a novel TP63 missense variant association with CRSwNP (OR = 1.519 [1.331-1.734]). Gene set analyses confirm enrichment of genes involved with type 2 inflammation, Jak-STAT signaling, and FOXP3 signaling. Our results highlight new shared and separate genetic pathways for CRSwNP and asthma. These provide several avenues of further investigation in functional and epidemiological follow-up, and evidence for immunological and non-immunological mechanisms behind both diseases.