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 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 ,   AMP-T2D-GENES Consortia, 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. 
Published: June 2021

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.