{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T13:51:48Z","timestamp":1780408308052,"version":"3.54.1"},"reference-count":63,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"vor","delay-in-days":35,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Cystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Using whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      In 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with statistically significant gene-based signals in\n                      <jats:italic>COL4A3<\/jats:italic>\n                      and (monoallelic)\n                      <jats:italic>PKHD1<\/jats:italic>\n                      . Quantification of disease risk for each gene (with replication in the separate UK Biobank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations, but suggested this category of variation contributes 3%\u20139% to the heritability of CyKD across European ancestries.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>By providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counseling in the clinic.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci181467","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T12:00:28Z","timestamp":1724760028000},"source":"Crossref","is-referenced-by-count":10,"title":["Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing"],"prefix":"10.1172","volume":"134","author":[{"given":"Omid","family":"Sadeghi-Alavijeh","sequence":"first","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie M.Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel T.","family":"Doctor","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalin D.","family":"Voinescu","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Stuckey","sequence":"additional","affiliation":[{"name":"Genomics England, Queen Mary University of London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Kousathanas","sequence":"additional","affiliation":[{"name":"Genomics England, Queen Mary University of London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander T.","family":"Ho","sequence":"additional","affiliation":[{"name":"Genomics England, Queen Mary University of London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horia C.","family":"Stanescu","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5878-941X","authenticated-orcid":true,"given":"Detlef","family":"Bockenhauer","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."},{"name":"University Hospital and Katholic University Leuven, Leuven, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard N.","family":"Sandford","sequence":"additional","affiliation":[{"name":"Academic Department of Medical Genetics, Cambridge University, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam P.","family":"Levine","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."},{"name":"Research Department of Pathology, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9170-1579","authenticated-orcid":true,"given":"Daniel P.","family":"Gale","sequence":"additional","affiliation":[{"name":"Centre for Kidney and Bladder Health, University College London, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,8,27]]},"reference":[{"issue":"suppl 1","key":"B1","first-page":"1","article-title":"UK renal registry 20th annual report: introduction","volume":"139","author":"Evans","year":"2018","journal-title":"Nephrology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018050493"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-10-2041-4_2"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.207"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.013"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.004"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2019030298"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.11.016"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.06.013"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfv456"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015010016"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2011101032"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22103"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2016.48"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1312543"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2434-2"},{"key":"B17","unstructured":"NIH. 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