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    Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

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    Author
    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, Josée
    Garay-Sevilla, Ma Eugenia
    García-Ortiz, Humberto
    Gieger, Christian
    Glaser, Benjamin
    González-Villalpando, Clicerio
    Gonzalez, Ma Elena
    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, Noël 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
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    Date
    2021-06-09
    Journal
    Nature Communications
    Publisher
    Springer Nature
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s41467-021-23556-4
    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.
    Keyword
    monogenic diseases
    Penetrance
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16004
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-021-23556-4
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