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Genetic factors other than CF-causing<jats:italic>CFTR<\/jats:italic>(CF transmembrane conductance regulator) variations contribute \u223c85% of the variation in chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to<jats:italic>P. aeruginosa<\/jats:italic>infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We conducted a genome-wide association study of chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98\u00d710<jats:sup>\u22128<\/jats:sup>) and rs927553 (chr13q12.12; p=1.91\u00d710<jats:sup>\u22128<\/jats:sup>) were associated with chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age (\u03b2=0.782\u2005years, p=4.24\u00d710<jats:sup>\u22124<\/jats:sup>). In the reverse direction, we observed a moderate effect (\u03b2=0.002, p=0.012).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified two novel loci that are associated with chronic<jats:italic>P. aeruginosa<\/jats:italic>infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between<jats:italic>P. aeruginosa<\/jats:italic>infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.00062-2024","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T15:06:23Z","timestamp":1723129583000},"page":"2400062","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Genome-wide association study of susceptibility to<i>Pseudomonas aeruginosa<\/i>infection in cystic fibrosis"],"prefix":"10.1183","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-2901","authenticated-orcid":false,"given":"Boxi","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiafen","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Keenan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-chung","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"M\u00e9sin\u00e8le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Calmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badreddine","family":"Mohand Oumoussa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Yves","family":"Bo\u00eblle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-7945","authenticated-orcid":false,"given":"Lo\u00efc","family":"Guillot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7026-7523","authenticated-orcid":false,"given":"Harriet","family":"Corvol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Waters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa J.","family":"Strug","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"2024120209203821000_64.5.2400062.1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200304-505SO"},{"key":"2024120209203821000_64.5.2400062.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008007"},{"key":"2024120209203821000_64.5.2400062.3","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1093\/jpids\/piac052","article-title":"Opportunistic pathogens in cystic fibrosis: epidemiology and pathogenesis of lung infection","volume":"11","author":"Blanchard","year":"2022","journal-title":"J Pediatric Infect Dis Soc"},{"key":"2024120209203821000_64.5.2400062.4","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.2009.abs"},{"key":"2024120209203821000_64.5.2400062.5","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.23715"},{"key":"2024120209203821000_64.5.2400062.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2021.09.017"},{"key":"2024120209203821000_64.5.2400062.7","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.10127"},{"key":"2024120209203821000_64.5.2400062.8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03067"},{"key":"2024120209203821000_64.5.2400062.9","unstructured":"Cystic Fibrosis Canada . 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