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oai:repisalud.isciii.es:20.500.12105/147372025-05-08T15:00:20Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19613
Repisalud author Goodrich, Julia K author Singer-Berk, Moriel author Son, Rachel author Sveden, Abigail author Wood, Jordan author England, Eleina author Cole, Joanne B author Weisburd, Ben author Watts, Nick author Caulkins, Lizz author Dornbos, Peter author Koesterer, Ryan author Zappala, Zachary author Zhang, Haichen author Maloney, Kristin A author Dahl, Andy author Aguilar-Salinas, Carlos A author Atzmon, Gil author Barajas-Olmos, Francisco author Barzilai, Nir author Blangero, John author Boerwinkle, Eric author Bonnycastle, Lori L author Bottinger, Erwin author Bowden, Donald W author Centeno-Cruz, Federico author Chambers, John C author Chami, Nathalie author Chan, Edmund author Chan, Juliana author Cheng, Ching-Yu author Cho, Yoon Shin author Contreras-Cubas, Cecilia author Córdova, Emilio author Correa, Adolfo author DeFronzo, Ralph A author Duggirala, Ravindranath author Dupuis, Josée author Garay-Sevilla, María Eugenia author García-Ortiz, Humberto author Gieger, Christian author Glaser, Benjamin author González-Villalpando, Clicerio author Gonzalez, Ma Elena author Grarup, Niels author Groop, Leif author Gross, Myron author Haiman, Christopher author Han, Sohee author Hanis, Craig L author Hansen, Torben author Heard-Costa, Nancy L author Henderson, Brian E author Malacara Hernández, Juan Manuel author Hwang, Mi Yeong author Islas-Andrade, Sergio author Jørgensen, Marit E author Kang, Hyun Min author Kim, Bong-Jo author Kim, Young Jin author Koistinen, Heikki A author Kooner, Jaspal Singh author Kuusisto, Johanna author Kwak, Soo-Heon author Laakso, Markku author Lange, Leslie author Lee, Jong-Young author Lee, Juyoung author Lehman, Donna M author Linneberg, Allan author Liu, Jianjun author Loos, Ruth J F author Lyssenko, Valeriya author Ma, Ronald CW author Martínez-Hernández, Angélica author Meigs, James B author Meitinger, Thomas author Mendoza-Caamal, Elvia author Mohlke, Karen L author Morris, Andrew D author Morrison, Alanna C author Ng, Maggie C Y author Nilsson, Peter M author O'Donnell, Christopher J author Orozco, Lorena author Palmer, Colin NA author Park, Kyong Soo author Post, Wendy S author Pedersen, Oluf author Preuss, Michael author Psaty, Bruce M author Reiner, Alexander P author Revilla-Monsalve, Cristina author Rich, Stephen S author Rotter, Jerome I author Saleheen, Danish author Schurmann, Claudia author Sim, Xueling author Sladek, Rob author Small, Kerrin S author So, Wing Yee author Spector, Timothy D author Strauch, Konstantin author Strom, Tim M author Tai, E-Shyong author Tam, Claudia H T author Teo, Yik Ying author Thameem, Farook author Tomlinson, Brian author Tracy, Russell P author Tuomi, Tiinamaija author Tuomilehto, Jaakko author Tusié-Luna, Teresa author van Dam, Rob M author Vasan, Ramachandran S author Wilson, James G author Witte, Daniel R author Wong, Tien-Yin author Burtt, Noël P author Zaitlen, Noah author McCarthy, Mark I author Boehnke, Michael author Pollin, Toni I author Flannick, Jason author Mercader, Josep M author O'Donnell-Luria, Anne author Baxter, Samantha author Florez, Jose C author MacArthur, Daniel G author Udler, Miriam S author AMP-T2D-GENES Consortia funder NIH - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Estados Unidos) funder NIH - National Institute of Child Health and Human Development (NICHD) (Estados Unidos) funder American Diabetes Association 2022-07-20T08:50:49Z 2022-07-20T08:50:49Z 2021-06-09 Nat Commun. 2021 Jun 9;12(1):3505. 10.1038/s41467-021-23556-4 2041-1723 Nature Communications 34108472 http://hdl.handle.net/20.500.12105/14737 Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias. eng Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes research article 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 URL https://repisalud.isciii.es/bitstreams/ce7c706e-643e-4b42-a240-3335c5eb6a60/download File MD5 740f610817e46611fedd939a5bb13ffe 2746863 application/pdf DeterminantsOfPenetranceAnd_2021.pdf URL https://repisalud.isciii.es/bitstreams/9ad69c22-b9be-4d97-b5a1-c260b991f952/download File MD5 3bdccff2882894df7d38f16a4f24dd10 12655 application/vnd.openxmlformats-officedocument.wordprocessingml.document DeterminantsOfPenetranceAndDescriptionsOfAdditionalSupplementaryFiles_2021.docx URL https://repisalud.isciii.es/bitstreams/6d049029-2733-47ee-a07c-380df6aef01a/download File MD5 db1fbdb2809a7c9cc6f563af87fb6071 368695 application/pdf DeterminantsOfPenetranceAndReportingSummary_2021.pdf URL https://repisalud.isciii.es/bitstreams/69ef5d1b-cc5d-4931-8a1f-b7d686b346a4/download File MD5 024a18f9454a3bc5b8d11e7fa5a1d2b4 180308 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet DeterminantsOfPenetranceAndSupplementaryData_2021.xlsx URL https://repisalud.isciii.es/bitstreams/d7f93414-f247-4b4b-bb6e-fc4dcb7700b0/download File MD5 d210831b33806ed81e573173021c8191 933636 application/pdf DeterminantsOfPenetranceAndSupplementaryInformation_2021.pdf URL https://repisalud.isciii.es/bitstreams/314c2693-07d0-4d08-b5c3-a782e51b99f1/download File MD5 755a3580a0abbac72b4805303cfb470d 105662 text/plain DeterminantsOfPenetranceAnd_2021.pdf.txt URL https://repisalud.isciii.es/bitstreams/459f45e9-b26d-4160-b5d4-a5109c894dc5/download File MD5 de76f92411d669880bd1128399ef7d27 3643 text/plain DeterminantsOfPenetranceAndReportingSummary_2021.pdf.txt URL https://repisalud.isciii.es/bitstreams/33893ebf-947a-42b2-8acc-5ab1c4242736/download File MD5 485fdab31c67925ebeb08505744dcad7 75602 text/plain DeterminantsOfPenetranceAndSupplementaryInformation_2021.pdf.txt URL https://repisalud.isciii.es/bitstreams/fb1c007d-7444-4a07-b72e-9adc21937bfd/download File MD5 fec1bbddba956645f4892e1603cfeb93 784 text/plain DeterminantsOfPenetranceAndDescriptionsOfAdditionalSupplementaryFiles_2021.docx.txt URL https://repisalud.isciii.es/bitstreams/04a0c4d0-f973-4cf7-b05e-bc3e64bd6487/download File MD5 d5d50a3de53f03c8bfd592f9617c9a4b 100124 text/plain DeterminantsOfPenetranceAndSupplementaryData_2021.xlsx.txt