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https://doi.org/10.1038/s41467-021-23556-4
Title: | Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes |
Authors: | Goodrich, Julia K. Singer-Berk, Moriel Son, Rachel Sveden, Abigail Wood, Jordan England, Eleina Cole, Joanne B. Weisburd, Ben Watts, Nick Caulkins, Lizz Dornbos, Peter Koesterer, Ryan Zappala, Zachary Zhang, Haichen Maloney, Kristin A. Dahl, Andy Aguilar-Salinas, Carlos A. Atzmon, Gil Barajas-Olmos, Francisco Barzilai, Nir Blangero, John Boerwinkle, Eric Bonnycastle, Lori L. Bottinger, Erwin Bowden, Donald W. Centeno-Cruz, Federico Chambers, John C. Chami, Nathalie Chan, Edmund Chan, Juliana Cheng, Ching-Yu Cho, Yoon Shin Contreras-Cubas, Cecilia Córdova, Emilio Correa, Adolfo DeFronzo, Ralph A. Duggirala, Ravindranath Dupuis, Josee Eugenia Garay-Sevilla, Ma García-Ortiz, Humberto Gieger, Christian Glaser, Benjamin González-Villalpando, Clicerio Elena Gonzalez, Ma Grarup, Niels Groop, Leif Gross, Myron Haiman, Christopher Han, Sohee Hanis, Craig L. Hansen, Torben Heard-Costa, Nancy L. Henderson, Brian E. Hernandez, Juan Manuel Malacara Hwang, Mi Yeong Islas-Andrade, Sergio Jørgensen, Marit E. Kang, Hyun Min Kim, Bong-Jo Kim, Young Jin Koistinen, Heikki A. Kooner, Jaspal Singh Kuusisto, Johanna Kwak, Soo-Heon Laakso, Markku Lange, Leslie Lee, Jong-Young Lee, Juyoung Lehman, Donna M. Linneberg, Allan Liu, Jianjun Loos, Ruth J. F. Lyssenko, Valeriya Ma, Ronald C. W. Martínez-Hernández, Angélica Meigs, James B. Meitinger, Thomas Mendoza-Caamal, Elvia Mohlke, Karen L. Morris, Andrew D. Morrison, Alanna C. Ng, Maggie C. Y. Nilsson, Peter M. O’Donnell, Christopher J. Orozco, Lorena Palmer, Colin N. A. Park, Kyong Soo Post, Wendy S. Pedersen, Oluf Preuss, Michael Psaty, Bruce M. Reiner, Alexander P. Revilla-Monsalve, Cristina Rich, Stephen S. Rotter, Jerome I. Saleheen, Danish Schurmann, Claudia Sim, Xueling Sladek, Rob Small, Kerrin S. So, Wing Yee Spector, Timothy D. Strauch, Konstantin Strom, Tim M. Tai, E. Shyong Tam, Claudia H. T. Teo, Yik Ying Thameem, Farook Tomlinson, Brian Tracy, Russell P. Tuomi, Tiinamaija Tuomilehto, Jaakko Tusié-Luna, Teresa van Dam, Rob M. Vasan, Ramachandran S. Wilson, James G. Witte, Daniel R. Wong, Tien-Yin Burtt, Noel P. Zaitlen, Noah McCarthy, Mark I. Boehnke, Michael Pollin, Toni I. Flannick, Jason Mercader, Josep M. O’Donnell-Luria, Anne Baxter, Samantha Florez, Jose C. MacArthur, Daniel G. Udler, Miriam S. |
Issue Date: | 9-Jun-2021 |
Publisher: | Nature Research |
Citation: | Goodrich, Julia K., Singer-Berk, Moriel, Son, Rachel, Sveden, Abigail, Wood, Jordan, England, Eleina, Cole, Joanne B., Weisburd, Ben, Watts, Nick, Caulkins, Lizz, Dornbos, Peter, Koesterer, Ryan, Zappala, Zachary, Zhang, Haichen, Maloney, Kristin A., Dahl, Andy, Aguilar-Salinas, Carlos A., Atzmon, Gil, Barajas-Olmos, Francisco, Barzilai, Nir, Blangero, John, Boerwinkle, Eric, Bonnycastle, Lori L., Bottinger, Erwin, Bowden, Donald W., Centeno-Cruz, Federico, Chambers, John C., Chami, Nathalie, Chan, Edmund, Chan, Juliana, Cheng, Ching-Yu, Cho, Yoon Shin, Contreras-Cubas, Cecilia, Córdova, Emilio, Correa, Adolfo, DeFronzo, Ralph A., Duggirala, Ravindranath, Dupuis, Josee, Eugenia Garay-Sevilla, Ma, García-Ortiz, Humberto, Gieger, Christian, Glaser, Benjamin, González-Villalpando, Clicerio, Elena Gonzalez, Ma, Grarup, Niels, Groop, Leif, Gross, Myron, Haiman, Christopher, Han, Sohee, Hanis, Craig L., Hansen, Torben, Heard-Costa, Nancy L., Henderson, Brian E., Hernandez, Juan Manuel Malacara, Hwang, Mi Yeong, Islas-Andrade, Sergio, Jørgensen, Marit E., Kang, Hyun Min, Kim, Bong-Jo, Kim, Young Jin, Koistinen, Heikki A., Kooner, Jaspal Singh, Kuusisto, Johanna, Kwak, Soo-Heon, Laakso, Markku, Lange, Leslie, Lee, Jong-Young, Lee, Juyoung, Lehman, Donna M., Linneberg, Allan, Liu, Jianjun, Loos, Ruth J. F., Lyssenko, Valeriya, Ma, Ronald C. W., Martínez-Hernández, Angélica, Meigs, James B., Meitinger, Thomas, Mendoza-Caamal, Elvia, Mohlke, Karen L., Morris, Andrew D., Morrison, Alanna C., Ng, Maggie C. Y., Nilsson, Peter M., O’Donnell, Christopher J., Orozco, Lorena, Palmer, Colin N. A., Park, Kyong Soo, Post, Wendy S., Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M., Reiner, Alexander P., Revilla-Monsalve, Cristina, Rich, Stephen S., Rotter, Jerome I., Saleheen, Danish, Schurmann, Claudia, Sim, Xueling, Sladek, Rob, Small, Kerrin S., So, Wing Yee, Spector, Timothy D., Strauch, Konstantin, Strom, Tim M., Tai, E. Shyong, Tam, Claudia H. T., Teo, Yik Ying, Thameem, Farook, Tomlinson, Brian, Tracy, Russell P., Tuomi, Tiinamaija, Tuomilehto, Jaakko, Tusié-Luna, Teresa, van Dam, Rob M., Vasan, Ramachandran S., Wilson, James G., Witte, Daniel R., Wong, Tien-Yin, Burtt, Noel P., Zaitlen, Noah, McCarthy, Mark I., Boehnke, Michael, Pollin, Toni I., Flannick, Jason, Mercader, Josep M., O’Donnell-Luria, Anne, Baxter, Samantha, Florez, Jose C., MacArthur, Daniel G., Udler, Miriam S. (2021-06-09). Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. Nature Communications 12 (1) : 3505. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-021-23556-4 |
Rights: | Attribution 4.0 International |
Abstract: | 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. © 2021, The Author(s). |
Source Title: | Nature Communications |
URI: | https://scholarbank.nus.edu.sg/handle/10635/233573 |
ISSN: | 2041-1723 |
DOI: | 10.1038/s41467-021-23556-4 |
Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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