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Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared to common variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Rare variant polygenic risk scores identify individuals with outlier phenotypes in common human diseases and complex traits.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.05.01.23289356","type":"posted-content","created":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:26Z","timestamp":1683072026000},"source":"Crossref","is-referenced-by-count":1,"title":["Rare penetrant mutations confer severe risk of common diseases"],"prefix":"10.64898","author":[{"given":"Petko","family":"Fiziev","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy","family":"McRae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob C.","family":"Ulirsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline S.","family":"Dron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Hamp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanshen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierrick","family":"Wainschtein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zijian","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua G.","family":"Schraiber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan","family":"Cable","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yair","family":"Field","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Aguet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Fasnacht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Metwally","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Marques-Bonet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi L.","family":"Rehm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"O\u2019Donnell-Luria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit V.","family":"Khera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6947-8537","authenticated-orcid":false,"given":"Kyle Kai-How","family":"Farh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023051007451610000_2023.05.01.23289356v2.1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1120"},{"key":"2023051007451610000_2023.05.01.23289356v2.2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08494"},{"key":"2023051007451610000_2023.05.01.23289356v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00961-5"},{"key":"2023051007451610000_2023.05.01.23289356v2.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0379-x"},{"key":"2023051007451610000_2023.05.01.23289356v2.5","first-page":"1","article-title":"The genetics and screening of familial hypercholesterolaemia","volume":"23","year":"2016","journal-title":"J. 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