Please use this identifier to cite or link to this item: 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
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