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

Nature Communications, Vol. 12 (2021)

Keywords
Authors
  • Julia K. Goodrich
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Moriel Singer-Berk
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Rachel Son
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Abigail Sveden
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Jordan Wood
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Eleina England
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Joanne B. Cole
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Ben Weisburd
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Nick Watts
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Lizz Caulkins
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Peter Dornbos
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Ryan Koesterer
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Zachary Zappala
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Haichen Zhang
  • School of Medicine, University of Maryland Baltimore
  • Kristin A. Maloney
  • School of Medicine, University of Maryland Baltimore
  • Andy Dahl
  • Department of Neurology, UCLA
  • Carlos A. Aguilar-Salinas
  • Instituto Nacional de Ciencias Medicas y Nutricion
  • Gil Atzmon
  • Department of Medicine, Albert Einstein College of Medicine
  • Francisco Barajas-Olmos
  • Instituto Nacional de Medicina Genómica
  • Nir Barzilai
  • Department of Medicine, Albert Einstein College of Medicine
  • John Blangero
  • Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley
  • Eric Boerwinkle
  • Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
  • Lori L. Bonnycastle
  • Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health
  • Erwin Bottinger
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
  • Donald W. Bowden
  • Center for Diabetes Research, Wake Forest School of Medicine
  • Federico Centeno-Cruz
  • Instituto Nacional de Medicina Genómica
  • John C. Chambers
  • Department of Epidemiology and Biostatistics, Imperial College London
  • Nathalie Chami
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
  • Edmund Chan
  • Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
  • Juliana Chan
  • Department of Medicine and Therapeutics, The Chinese University of Hong Kong
  • Ching-Yu Cheng
  • Singapore Eye Research Institute, Singapore National Eye Centre
  • Yoon Shin Cho
  • Department of Biomedical Science, Hallym University
  • Cecilia Contreras-Cubas
  • Instituto Nacional de Medicina Genómica
  • Emilio Córdova
  • Instituto Nacional de Medicina Genómica
  • Adolfo Correa
  • Department of Medicine, University of Mississippi Medical Center
  • Ralph A. DeFronzo
  • Department of Medicine, University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio)
  • Ravindranath Duggirala
  • Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley
  • Josée Dupuis
  • Department of Biostatistics, Boston University School of Public Health
  • Ma Eugenia Garay-Sevilla
  • Department of Medical Science, División of Health Science, University of Guanjuato. Campus León. León
  • Humberto García-Ortiz
  • Instituto Nacional de Medicina Genómica
  • Christian Gieger
  • Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
  • Benjamin Glaser
  • Endocrinology and Metabolism Service, 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
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
  • Leif Groop
  • Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre
  • Myron Gross
  • Department of Laboratory Medicine and Pathology, University of Minnesota
  • Christopher Haiman
  • Department of Preventive Medicine, Keck School of Medicine of USC
  • Sohee Han
  • Division of Genome Research, Center for Genome Science, National Institute of Health
  • Craig L. Hanis
  • Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
  • Torben Hansen
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
  • Nancy L. Heard-Costa
  • Boston University and National Heart Lung and Blood Institute’s Framingham Heart Study
  • Brian E. Henderson
  • Department of Preventive Medicine, Keck School of Medicine of USC
  • Juan Manuel Malacara Hernandez
  • Department of Medical Science, División of Health Science, University of Guanjuato. Campus León. León
  • Mi Yeong Hwang
  • Division of Genome Research, Center for Genome Science, National Institute of Health
  • Sergio Islas-Andrade
  • Instituto Nacional de Medicina Genómica
  • Marit E. Jørgensen
  • Steno Diabetes Center Copenhagen
  • Hyun Min Kang
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan
  • Bong-Jo Kim
  • Division of Genome Research, Center for Genome Science, National Institute of Health
  • Young Jin Kim
  • Division of Genome Research, Center for Genome Science, National Institute of Health
  • Heikki A. Koistinen
  • Department of Public Health Solutions, Finnish Institute for Health and Welfare
  • Jaspal Singh Kooner
  • Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust
  • Johanna Kuusisto
  • Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital
  • Soo-Heon Kwak
  • Department of Internal Medicine, Seoul National University Hospital
  • Markku Laakso
  • Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital
  • Leslie Lange
  • Department of Medicine, University of Colorado Denver, Anschutz Medical Campus
  • Jong-Young Lee
  • Oneomics Soonchunhyang Mirae Medical Center
  • Juyoung Lee
  • Division of Genome Research, Center for Genome Science, National Institute of Health
  • Donna M. Lehman
  • Department of Medicine, University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio)
  • Allan Linneberg
  • Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
  • Jianjun Liu
  • Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
  • Ruth J. F. Loos
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
  • Valeriya Lyssenko
  • Centro de Estudios en Diabetes
  • Ronald C. W. Ma
  • Department of Medicine and Therapeutics, The Chinese University of Hong Kong
  • Angélica Martínez-Hernández
  • Instituto Nacional de Medicina Genómica
  • James B. Meigs
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Thomas Meitinger
  • Institute of Human Genetics, Technical University of Munich
  • Elvia Mendoza-Caamal
  • Instituto Nacional de Medicina Genómica
  • Karen L. Mohlke
  • Department of Genetics, University of North Carolina Chapel Hill
  • Andrew D. Morris
  • Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford
  • Alanna C. Morrison
  • Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
  • Maggie C. Y. Ng
  • Center for Diabetes Research, Wake Forest School of Medicine
  • Peter M. Nilsson
  • Department of Clinical Sciences, Medicine, Lund University
  • Christopher J. O’Donnell
  • Department of Pediatrics, Harvard Medical School
  • Lorena Orozco
  • Instituto Nacional de Medicina Genómica
  • Colin N. A. Palmer
  • Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, University of Dundee
  • Kyong Soo Park
  • Department of Internal Medicine, Seoul National University Hospital
  • Wendy S. Post
  • Division of Cardiology, Department of Medicine, Johns Hopkins University
  • Oluf Pedersen
  • Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
  • Michael Preuss
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
  • Bruce M. Psaty
  • Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington
  • Alexander P. Reiner
  • Fred Hutchinson Cancer Research Center
  • Cristina Revilla-Monsalve
  • Instituto Nacional de Medicina Genómica
  • Stephen S. Rich
  • Center for Public Health Genomics, 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
  • Division of Translational Medicine and Human Genetics, University of Pennsylvania
  • Claudia Schurmann
  • The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
  • Xueling Sim
  • Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
  • Rob Sladek
  • Department of Human Genetics, McGill University
  • Kerrin S. Small
  • Department of Twin Research and Genetic Epidemiology, King’s College London
  • Wing Yee So
  • Department of Medicine and Therapeutics, The Chinese University of Hong Kong
  • Timothy D. Spector
  • Department of Twin Research and Genetic Epidemiology, King’s College London
  • Konstantin Strauch
  • Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health
  • Tim M. Strom
  • Institute of Human Genetics, Technical University of Munich
  • E. Shyong Tai
  • Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
  • Claudia H. T. Tam
  • Department of Medicine and Therapeutics, The Chinese University of Hong Kong
  • Yik Ying Teo
  • Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
  • Farook Thameem
  • Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University
  • Brian Tomlinson
  • Faculty of Medicine, Macau University of Science & Technology
  • Russell P. Tracy
  • Department of Pathology and Laboratory Medicine, The Robert Larner M.D. College of Medicine, University of Vermont
  • Tiinamaija Tuomi
  • Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre
  • Jaakko Tuomilehto
  • Public Health Promotion Unit, 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. van Dam
  • Department of Medicine, Yong Loo Lin School of Medicine, 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
  • Department of Physiology and Biophysics, University of Mississippi Medical Center
  • Daniel R. Witte
  • Department of Public Health, Aarhus University
  • Tien-Yin Wong
  • Singapore Eye Research Institute, Singapore National Eye Centre
  • AMP-T2D-GENES Consortia
  • Noël P. Burtt
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Noah Zaitlen
  • Department of Neurology, UCLA
  • Mark I. McCarthy
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford
  • Michael Boehnke
  • Department of Biostatistics and Center for Statistical Genetics, University of Michigan
  • Toni I. Pollin
  • School of Medicine, University of Maryland Baltimore
  • Jason Flannick
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Josep M. Mercader
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Anne O’Donnell-Luria
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Samantha Baxter
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Jose C. Florez
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Daniel G. MacArthur
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
  • Miriam S. Udler
  • Program in Medical and Population Genetics, Broad Institute of MIT and Harvard

Abstract

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

Read more: fulltext (HTML)