131 genetic loci highlight immunological pathways and tissues in nasal polyposis and asthma.

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.