{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,1,25]],"date-time":"2025-01-25T20:40:02Z","timestamp":1737837602153,"version":"3.33.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"am","delay-in-days":365,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM134005"],"award-info":[{"award-number":["R01 GM134005"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DMS 1902903"],"award-info":[{"award-number":["DMS 1902903"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Quant. Biol."],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Whole\u2010exome sequencing (WES) studies have identified multiple genes enriched for <jats:italic>de novo<\/jats:italic> mutations (DNMs) in congenital heart disease (CHD) probands. However, risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this manuscript, we introduce a hierarchical Bayesian framework for gene\u2010level association test which jointly analyzes <jats:italic>de novo<\/jats:italic> and rare transmitted variants. Through integrative modeling of multiple types of genetic variants, gene\u2010level annotations, and reference data from large population cohorts, our method accurately characterizes the expected frequencies of both <jats:italic>de novo<\/jats:italic> and transmitted variants and shows improved statistical power compared to analyses based on DNMs only.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Applied to WES data of 2,645 CHD proband\u2010parent trios, our method identified 15 significant genes, half of which are novel, leading to new insights into the genetic bases of CHD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results showcase the power of integrative analysis of transmitted and <jats:italic>de novo<\/jats:italic> variants for disease gene discovery.<\/jats:p><\/jats:sec>","DOI":"10.15302\/j-qb-021-0248","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T01:55:40Z","timestamp":1620266140000},"page":"216-227","source":"Crossref","is-referenced-by-count":3,"title":["Integrative modeling of transmitted and <i>de novo<\/i> variants identifies novel risk genes for congenital heart disease"],"prefix":"10.1002","volume":"9","author":[{"given":"Mo","family":"Li","sequence":"first","affiliation":[{"name":"<!--1--> Department of Biostatistics Yale School of Public Health New Haven CT 06510 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Zeng","sequence":"additional","affiliation":[{"name":"<!--2--> Department of Genetics Yale University New Haven CT 06510 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chentian","family":"Jin","sequence":"additional","affiliation":[{"name":"<!--3--> Department of Molecular Cellular &amp; Developmental Biology Yale University New Haven CT 06510 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng Chih","family":"Jin","sequence":"additional","affiliation":[{"name":"<!--4--> Department of Genetics Washington University School of Medicine St Louis MO 63110 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weilai","family":"Dong","sequence":"additional","affiliation":[{"name":"<!--2--> Department of Genetics Yale University New Haven CT 06510 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Brueckner","sequence":"additional","affiliation":[{"name":"<!--2--> Department of Genetics Yale University New Haven CT 06510 USA"},{"name":"<!--5--> Department of Pediatrics Yale University New Haven CT 06510 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Lifton","sequence":"additional","affiliation":[{"name":"<!--2--> Department of Genetics Yale University New Haven CT 06510 USA"},{"name":"<!--6--> Laboratory of Human Genetics and Genomics Rockefeller University New York NY 10065 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiongshi","family":"Lu","sequence":"additional","affiliation":[{"name":"<!--7--> Department of Biostatistics and Medical Informatics University of Wisconsin\u2010Madison Madison WI 53792 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"<!--1--> Department of Biostatistics Yale School of Public Health New Haven CT 06510 USA"},{"name":"<!--2--> Department of Genetics Yale University New Haven CT 06510 USA"},{"name":"<!--8--> Program of Computational Biology and Bioinformatics Yale University New Haven CT 06510 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