{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T01:36:12Z","timestamp":1768872972006,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,5]]},"group-title":"Genetic and Genomic Medicine","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Genetic mutations that yield defective cystic fibrosis transmembrane regulator (\n                  <jats:italic>CFTR<\/jats:italic>\n                  ) protein cause cystic fibrosis, a life-limiting autosomal recessive Mendelian disorder. A protective role of\n                  <jats:italic>CFTR<\/jats:italic>\n                  loss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging the largest IBD exome sequencing dataset to date, comprising 38,558 cases and 66,945 controls in the discovery stage, and 35,797 cases and 179,942 controls in the replication stage, we established a protective role of CF-risk variants against IBD based on evidence from the association test of\n                  <jats:italic>CFTR<\/jats:italic>\n                  delF508 (p-value=8.96E-11) and the gene-based burden test of CF-risk variants (p-value=3.9E-07). Furthermore, we assessed variant prioritization methods, including AlphaMissense, using clinically annotated CF-risk variants as the gold standard. Our findings highlight the critical and unmet need for effective variant prioritization in gene-based burden tests.\n                <\/jats:p>","DOI":"10.1101\/2024.12.02.24318364","type":"posted-content","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T18:45:24Z","timestamp":1733424324000},"source":"Crossref","is-referenced-by-count":3,"title":["Cystic fibrosis risk variants confer protection against inflammatory bowel disease"],"prefix":"10.64898","author":[{"given":"Mingrui","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksejs","family":"Sazonovs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2621-2234","authenticated-orcid":false,"given":"Christine","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Fachal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the International Inflammatory Bowel Disease Genetics Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl A.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0949-8752","authenticated-orcid":false,"given":"Mark J.","family":"Daly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailiang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024120704000706000_2024.12.02.24318364v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90353-R"},{"key":"2024120704000706000_2024.12.02.24318364v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1712984"},{"key":"2024120704000706000_2024.12.02.24318364v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90148-8"},{"key":"2024120704000706000_2024.12.02.24318364v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03540-9"},{"key":"2024120704000706000_2024.12.02.24318364v1.5","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0250OC"},{"key":"2024120704000706000_2024.12.02.24318364v1.6","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7614com"},{"key":"2024120704000706000_2024.12.02.24318364v1.7","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.23.3.3949"},{"key":"2024120704000706000_2024.12.02.24318364v1.8","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1038\/s41385-018-0013-8","article-title":"Increased intracellular Cl concentration promotes ongoing inflammation in airway epithelium","volume":"11","year":"2018","journal-title":"Mucosal Immunol"},{"key":"2024120704000706000_2024.12.02.24318364v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccm.2015.11.010"},{"key":"2024120704000706000_2024.12.02.24318364v1.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075667"},{"key":"2024120704000706000_2024.12.02.24318364v1.11","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1159\/000446840","article-title":"Current Concepts and Controversies in Innate Immunity of Cystic Fibrosis Lung Disease","volume":"8","year":"2016","journal-title":"J. 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