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

By Julia Goodrich, Moriel Singer-Berk, Rachel Son, Abigail Sveden, Jordan Wood, Eleina England, Joanne B. Cole, Ben Weisburd, Nick Watts, Zachary Zappala, Haichen Zhang, Kristin A. Maloney, Andy Dahl, Carlos A Aguilar-Salinas, Gil Atzmon, Francisco Barajas-Olmos, Nir Barzilai, John Blangero, Eric Boerwinkle, Lori L Bonnycastle, Erwin Bottinger, Donald W Bowden, Federico Centeno- Cruz, John C Chambers, Nathalie Chami, Edmund Chan, Juliana Chan, Ching-Yu Cheng, Yoon Shin Cho, Cecilia Contreras-Cubas, Emilio Cordova, Adolfo Correa, Ralph A DeFronzo, Ravindranath Duggirala, Josee Dupuis, Ma. Eugenia Garay-Sevilla, Humberto Garcia-Ortiz, Christian Gieger, Benjamin Glaser Glaser, Clicerio Gonzalez-Villalpando, Ma Elena Gonzalez, Niels Grarup, Leif Groop, Myron Gross, Christopher Haiman, Sohee Han, Craig L Hanis, Torben Hansen, Nancy L. Heard-Costa, Brian E Henderson, Juan Manuel Malacara Hernandez, Mi Yeong Hwang, Sergio Islas-Andrade, Marit E Jorgensen, Hyun Min Kang, Bong-Jo Kim, Young Jin Kim, Heikki A Koistinen, Jaspal Singh Kooner, Johanna Kuusisto, Soo-Heon Kwak, Markku Laakso, Leslie Lange, Jong-Young Lee, Juyoung Lee, Donna M. Lehman, Allan Linneberg, Jianjun Liu, Ruth JF Loos, Valeriya Lyssenko, Ronald C. W. Ma, Angelica Martinez-Hernandez, James B Meigs, Thomas Meitinger, Elvia Mendoza- Caamal, Karen L. Mohlke, Andrew D Morris, Alanna C. Morrison, Maggie C.Y. Ng, Peter M Nilsson, Christopher J. ODonnell, Lorena Orozco, Colin N A Palmer, Kyong Soo Park, Wendy S. Post, Oluf Pedersen, Michael Preuss, Bruce M Psaty, Alexander P Reiner, Cristina Revilla-Monsalve, Stephen S Rich, Jerome I. Rotter, Danish Saleheen, Claudia Schurmann, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Xavier Soberon, Timothy D. Spector, Konstantin Strauch, Tim M Strom, E Shyong Tai, Claudia HT Tam, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Russell P Tracy, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusie-Luna, Rob M van Dam, Ramachandran S Vasan, James G Wilson, Daniel R Witte, Tien-Yin Wong, Lizz Caulkins, Noel P Burtt, Noah Zaitlen, Mark I. McCarthy, Michael Boehnke, Toni I. Pollin, Jason Flannick, Josep M. Mercader, Anne ODonnell-Luria, Samantha Baxter, Jose C. Florez, Daniel MacArthur, Miriam Udler, for AMP-T2D-GENES

Posted 24 Sep 2020
medRxiv DOI: 10.1101/2020.09.22.20195529

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop 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 applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.

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