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

Julia K. Goodrich, Moriel Singer-Berk, Rachel Son, Abigail Sveden, Jordan Wood, Eleina England, Joanne B. Cole, Ben Weisburd, Nick Watts, Lizz Caulkins, Peter Dornbos, Ryan Koesterer, 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 Córdova, Adolfo Correa, Ralph A. DeFronzo, Ravindranath Duggirala, Josée Dupuis, Ma Eugenia Garay-Sevilla, Humberto García-Ortiz, Christian Gieger, Benjamin Glaser, Clicerio González-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. Jørgensen, 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 J. F. Loos, Valeriya Lyssenko, Ronald C. W. Ma, Angélica Martínez-Hernández, 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. O’Donnell, 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, Timothy D. Spector, Konstantin Strauch, Tim M. Strom, E. Shyong Tai, Claudia H. T. Tam, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Russell P. Tracy, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Rob M. Dam, Ramachandran S. Vasan, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, Noël P. Burtt, Noah Zaitlen, Mark I. McCarthy, Michael Boehnke, Toni I. Pollin, Jason Flannick, Josep M. Mercader, Anne O’Donnell-Luria, Samantha Baxter, Jose C. Florez, Daniel G. MacArthur and Miriam S. Udler ()
Additional contact information
Julia K. Goodrich: Broad Institute of MIT and Harvard
Moriel Singer-Berk: Broad Institute of MIT and Harvard
Rachel Son: Broad Institute of MIT and Harvard
Abigail Sveden: Broad Institute of MIT and Harvard
Jordan Wood: Broad Institute of MIT and Harvard
Eleina England: Broad Institute of MIT and Harvard
Joanne B. Cole: Broad Institute of MIT and Harvard
Ben Weisburd: Broad Institute of MIT and Harvard
Nick Watts: Broad Institute of MIT and Harvard
Lizz Caulkins: Broad Institute of MIT and Harvard
Peter Dornbos: Broad Institute of MIT and Harvard
Ryan Koesterer: Broad Institute of MIT and Harvard
Zachary Zappala: Broad Institute of MIT and Harvard
Haichen Zhang: University of Maryland Baltimore
Kristin A. Maloney: University of Maryland Baltimore
Andy Dahl: UCLA
Carlos A. Aguilar-Salinas: Instituto Nacional de Ciencias Medicas y Nutricion
Gil Atzmon: Albert Einstein College of Medicine
Francisco Barajas-Olmos: Instituto Nacional de Medicina Genómica
Nir Barzilai: Albert Einstein College of Medicine
John Blangero: University of Texas Rio Grande Valley
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Lori L. Bonnycastle: National Institutes of Health
Erwin Bottinger: Icahn School of Medicine at Mount Sinai
Donald W. Bowden: Wake Forest School of Medicine
Federico Centeno-Cruz: Instituto Nacional de Medicina Genómica
John C. Chambers: Imperial College London
Nathalie Chami: Icahn School of Medicine at Mount Sinai
Edmund Chan: National University of Singapore and National University Health System
Juliana Chan: The Chinese University of Hong Kong
Ching-Yu Cheng: Singapore National Eye Centre
Yoon Shin Cho: Hallym University
Cecilia Contreras-Cubas: Instituto Nacional de Medicina Genómica
Emilio Córdova: Instituto Nacional de Medicina Genómica
Adolfo Correa: University of Mississippi Medical Center
Ralph A. DeFronzo: University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio)
Ravindranath Duggirala: University of Texas Rio Grande Valley
Josée Dupuis: Boston University School of Public Health
Ma Eugenia Garay-Sevilla: University of Guanjuato. Campus León. León
Humberto García-Ortiz: Instituto Nacional de Medicina Genómica
Christian Gieger: German Research Center for Environmental Health
Benjamin Glaser: Hadassah-Hebrew University Medical Center
Clicerio González-Villalpando: Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Publica
Ma Elena Gonzalez: Centro de Estudios en Diabetes
Niels Grarup: University of Copenhagen
Leif Groop: Lund University Diabetes Centre
Myron Gross: University of Minnesota
Christopher Haiman: Keck School of Medicine of USC
Sohee Han: National Institute of Health
Craig L. Hanis: The University of Texas Health Science Center at Houston
Torben Hansen: University of Copenhagen
Nancy L. Heard-Costa: Boston University and National Heart Lung and Blood Institute’s Framingham Heart Study
Brian E. Henderson: Keck School of Medicine of USC
Juan Manuel Malacara Hernandez: University of Guanjuato. Campus León. León
Mi Yeong Hwang: National Institute of Health
Sergio Islas-Andrade: Instituto Nacional de Medicina Genómica
Marit E. Jørgensen: Steno Diabetes Center Copenhagen
Hyun Min Kang: University of Michigan
Bong-Jo Kim: National Institute of Health
Young Jin Kim: National Institute of Health
Heikki A. Koistinen: Finnish Institute for Health and Welfare
Jaspal Singh Kooner: London North West Healthcare NHS Trust
Johanna Kuusisto: University of Eastern Finland and Kuopio University Hospital
Soo-Heon Kwak: Seoul National University Hospital
Markku Laakso: University of Eastern Finland and Kuopio University Hospital
Leslie Lange: University of Colorado Denver, Anschutz Medical Campus
Jong-Young Lee: Oneomics Soonchunhyang Mirae Medical Center
Juyoung Lee: National Institute of Health
Donna M. Lehman: University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio)
Allan Linneberg: University of Copenhagen
Jianjun Liu: National University of Singapore and National University Health System
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Valeriya Lyssenko: Centro de Estudios en Diabetes
Ronald C. W. Ma: The Chinese University of Hong Kong
Angélica Martínez-Hernández: Instituto Nacional de Medicina Genómica
James B. Meigs: Broad Institute of MIT and Harvard
Thomas Meitinger: Technical University of Munich
Elvia Mendoza-Caamal: Instituto Nacional de Medicina Genómica
Karen L. Mohlke: University of North Carolina Chapel Hill
Andrew D. Morris: University of Oxford
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Maggie C. Y. Ng: Wake Forest School of Medicine
Peter M. Nilsson: Lund University
Christopher J. O’Donnell: Harvard Medical School
Lorena Orozco: Instituto Nacional de Medicina Genómica
Colin N. A. Palmer: University of Dundee
Kyong Soo Park: Seoul National University Hospital
Wendy S. Post: Johns Hopkins University
Oluf Pedersen: University of Copenhagen
Michael Preuss: Icahn School of Medicine at Mount Sinai
Bruce M. Psaty: University of Washington
Alexander P. Reiner: Fred Hutchinson Cancer Research Center
Cristina Revilla-Monsalve: Instituto Nacional de Medicina Genómica
Stephen S. Rich: University of Virginia School of Medicine
Jerome I. Rotter: The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation (formerly Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center
Danish Saleheen: University of Pennsylvania
Claudia Schurmann: Icahn School of Medicine at Mount Sinai
Xueling Sim: National University of Singapore and National University Health System
Rob Sladek: McGill University
Kerrin S. Small: King’s College London
Wing Yee So: The Chinese University of Hong Kong
Timothy D. Spector: King’s College London
Konstantin Strauch: German Research Center for Environmental Health
Tim M. Strom: Technical University of Munich
E. Shyong Tai: National University of Singapore and National University Health System
Claudia H. T. Tam: The Chinese University of Hong Kong
Yik Ying Teo: National University of Singapore and National University Health System
Farook Thameem: Kuwait University
Brian Tomlinson: Macau University of Science & Technology
Russell P. Tracy: University of Vermont
Tiinamaija Tuomi: Lund University Diabetes Centre
Jaakko Tuomilehto: Finnish Institute for Health and Welfare
Teresa Tusié-Luna: Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Rob M. Dam: National University of Singapore and National University Health System
Ramachandran S. Vasan: Boston University and National Heart Lung and Blood Institute’s Framingham Heart Study
James G. Wilson: University of Mississippi Medical Center
Daniel R. Witte: Aarhus University
Tien-Yin Wong: Singapore National Eye Centre
Noël P. Burtt: Broad Institute of MIT and Harvard
Noah Zaitlen: UCLA
Mark I. McCarthy: University of Oxford
Michael Boehnke: University of Michigan
Toni I. Pollin: University of Maryland Baltimore
Jason Flannick: Broad Institute of MIT and Harvard
Josep M. Mercader: Broad Institute of MIT and Harvard
Anne O’Donnell-Luria: Broad Institute of MIT and Harvard
Samantha Baxter: Broad Institute of MIT and Harvard
Jose C. Florez: Broad Institute of MIT and Harvard
Daniel G. MacArthur: Broad Institute of MIT and Harvard
Miriam S. Udler: Broad Institute of MIT and Harvard

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23556-4

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